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Zheng Z, Chen R, Liu M, Ding Y, Xu S, Hou C, Li S. Identification of Novel Therapeutic Targets for Hypertension. Hypertension 2025; 82:1056-1070. [PMID: 40109242 DOI: 10.1161/hypertensionaha.124.24277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 03/06/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Persistently high blood pressure remains the leading risk factor for mortality worldwide. This study aims to identify potential drug targets for hypertension. METHODS Mendelian randomization was used to identify therapeutic targets for hypertension. Genome-wide association study summary statistics were obtained from the UK Biobank and FinnGen study. Cis-expression quantitative trait loci from the eQTLGen Consortium served as genetic instruments. Colocalization analysis evaluated the likelihood of shared causal variants between single-nucleotide polymorphisms influencing hypertension and gene expression. Survival analysis of UK Biobank data assessed hypertension and mortality risks across participants with different gene alleles. RESULTS Mendelian randomization analysis identified 190 drug targets in the discovery cohort and 65 in the replication cohort after multiple testing correction. Colocalization analysis identified 14 hypertension-related drug targets, including ACE, AIMP1, CDC25A, EHMT2, FES, GPX1, GRK4, HSD3B7, NEK4, PTPN12, SIK2, SLC22A4, SLC2A4, and TNFSF12. Survival analysis revealed individuals with the A allele at rs4308 in the ACE gene had a higher incidence of hypertension, while those with the T allele at rs11242109 in the SLC22A4 gene showed a lower hypertension-specific mortality rate. CONCLUSIONS Drug target Mendelian randomization studies offer new directions for hypertension treatment, providing insights into its mechanisms and robust targets for developing antihypertensive drugs.
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Affiliation(s)
- Zhiwei Zheng
- School of Life Sciences, Beijing University of Chinese Medicine, China
| | - Rumeng Chen
- School of Life Sciences, Beijing University of Chinese Medicine, China
| | - Menghua Liu
- School of Life Sciences, Beijing University of Chinese Medicine, China
| | - Yining Ding
- School of Life Sciences, Beijing University of Chinese Medicine, China
| | - Shuling Xu
- School of Life Sciences, Beijing University of Chinese Medicine, China
| | - Chunyan Hou
- School of Life Sciences, Beijing University of Chinese Medicine, China
| | - Sen Li
- School of Life Sciences, Beijing University of Chinese Medicine, China
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Atamanchuk A, Pyrshev K, Kordysh M, Zaika O, Pochynyuk O. Intercalated Cell ClC-K2 Channel Contributes to Systemic Cl - Balance and Acid-Base Homeostasis. FASEB J 2025; 39:e70598. [PMID: 40366367 PMCID: PMC12083762 DOI: 10.1096/fj.202500588rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/08/2025] [Accepted: 04/24/2025] [Indexed: 05/15/2025]
Abstract
Maintaining systemic Cl- homeostasis plays a critical yet underappreciated role in setting the baseline and salt sensitivity of blood pressure. ClC-K2 Cl--permeable channel is localized on the basolateral membrane of the distal nephron segments. Impaired NaCl reabsorption in the thick ascending limb and distal convoluted tubule has been proposed as the underlying cause of polyuria and hypotension in patients with the Bartter's syndrome type 3 due to loss-of-function of the channel. However, the relevance of ClC-K2 in the collecting duct intercalated cells (ICs) for renal function and Cl- homeostasis remains obscure. Here, we compared the systemic manifestations and examined signaling components in ClC-K2fl/fl Pax8 (lacking ClC-K2 in renal nephron) and ClC-K2fl/fl B1 ATPase (lacking ClC-K2 in ICs) mice. ClC-K2fl/fl Pax8 mice exhibited hypotension, reduced glomerular filtration rate, urinary NaCl wasting, and metabolic alkalosis with hypokalemia, thereby recapitulating the phenotype of Bartter's syndrome. While ClC-K2 deletion in ICs did not affect urinary volume and baseline blood pressure, ClC-K2fl/fl B1 ATPase mice developed moderate hypotension in response to dietary Cl- deficiency. Decreased expression and impaired apical translocation of pendrin (Slc26A4) were causative for the augmented urinary Cl- excretion. Furthermore, ClC-K2 deletion in ICs interfered with the development of Angiotensin II-dependent hypertension. The reduced pendrin function, along with a compensatory upregulation of the epithelial Na+ channel, caused hypokalemic metabolic alkalosis in ClC-K2fl/fl B1 ATPase mice. In summary, we show that ClC-K2 activity in ICs of the collecting duct plays physiologically relevant roles in the regulation of systemic Cl- balance and acid-base homeostasis.
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Affiliation(s)
- Anna Atamanchuk
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Kyrylo Pyrshev
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Mariya Kordysh
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Oleg Zaika
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Oleh Pochynyuk
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
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Arendshorst WJ, Vendrov AE, Kumar N, Ganesh SK, Madamanchi NR. Oxidative Stress in Kidney Injury and Hypertension. Antioxidants (Basel) 2024; 13:1454. [PMID: 39765782 PMCID: PMC11672783 DOI: 10.3390/antiox13121454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/09/2024] [Accepted: 11/18/2024] [Indexed: 01/11/2025] Open
Abstract
Hypertension (HTN) is a major contributor to kidney damage, leading to conditions such as nephrosclerosis and hypertensive nephropathy, significant causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). HTN is also a risk factor for stroke and coronary heart disease. Oxidative stress, inflammation, and activation of the renin-angiotensin-aldosterone system (RAAS) play critical roles in causing kidney injury in HTN. Genetic and environmental factors influence the susceptibility to hypertensive renal damage, with African American populations having a higher tendency due to genetic variants. Managing blood pressure (BP) effectively with treatments targeting RAAS activation, oxidative stress, and inflammation is crucial in preventing renal damage and the progression of HTN-related CKD and ESRD. Interactions between genetic and environmental factors impacting kidney function abnormalities are central to HTN development. Animal studies indicate that genetic factors significantly influence BP regulation. Anti-natriuretic mechanisms can reset the pressure-natriuresis relationship, requiring a higher BP to excrete sodium matched to intake. Activation of intrarenal angiotensin II receptors contributes to sodium retention and high BP. In HTN, the gut microbiome can affect BP by influencing energy metabolism and inflammatory pathways. Animal models, such as the spontaneously hypertensive rat and the chronic angiotensin II infusion model, mirror human essential hypertension and highlight the significance of the kidney in HTN pathogenesis. Overproduction of reactive oxygen species (ROS) plays a crucial role in the development and progression of HTN, impacting renal function and BP regulation. Targeting specific NADPH oxidase (NOX) isoforms to inhibit ROS production and enhance antioxidant mechanisms may improve renal structure and function while lowering blood pressure. Therapies like SGLT2 inhibitors and mineralocorticoid receptor antagonists have shown promise in reducing oxidative stress, inflammation, and RAAS activity, offering renal and antihypertensive protection in managing HTN and CKD. This review emphasizes the critical role of NOX in the development and progression of HTN, focusing on its impact on renal function and BP regulation. Effective BP management and targeting oxidative stress, inflammation, and RAAS activation, is crucial in preventing renal damage and the progression of HTN-related CKD and ESRD.
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Affiliation(s)
- Willaim J. Arendshorst
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA;
| | - Aleksandr E. Vendrov
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (A.E.V.); (N.K.); (S.K.G.)
| | - Nitin Kumar
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (A.E.V.); (N.K.); (S.K.G.)
- Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Santhi K. Ganesh
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (A.E.V.); (N.K.); (S.K.G.)
- Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nageswara R. Madamanchi
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (A.E.V.); (N.K.); (S.K.G.)
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Ralph DL, Ha D, Lei H, Priver TS, Smith SD, McFarlin BE, Schwindt S, Pandya D, Koepsell H, Pastor-Soler NM, Edwards A, McDonough AA. Potassium-Alkali-Enriched Diet, Hypertension, and Proteinuria following Uninephrectomy. J Am Soc Nephrol 2024; 35:1330-1350. [PMID: 38913441 PMCID: PMC11452139 DOI: 10.1681/asn.0000000000000420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 06/10/2024] [Indexed: 06/26/2024] Open
Abstract
Key Points A K-alkali–enriched diet blunted post-uninephrectomy hypertension and facilitated acid clearance by suppressing Na+ reabsorption. Uninephrectomy-associated proteinuria could be attributed to elevated single-nephron GFR and downregulation of megalin, which reduced fractional protein endocytosis. Background Losing or donating a kidney is associated with risks of developing hypertension and albuminuria. Few studies address mechanisms or interventions. We investigate the potential benefits of a K+- alkali–enriched diet and the mechanisms underlying proteinuria. Methods Male Sprague Dawley rats were fed either a 2% NaCl+0.95% KCl diet (HNa-LK) or a 0.74% NaCl+3% K+-alkali diet (HK-alk) for 3 weeks before uninephrectomy and then maintained on respective diets for 12 weeks. BP (by tail-cuff), urine, blood, and kidney proteins were analyzed before and after uninephrectomy. Results Before uninephrectomy, HK-alk–fed versus HNa-LK–fed rats exhibited similar BPs and plasma [K+], [Na+], but lower proximal (NHE3, sodium bicarbonate cotransporter 1, NaPi2) and higher distal (NCC, ENaC, and pendrin) transporter abundance, a pattern facilitating K+ and HCO3− secretion. After uninephrectomy, single-nephron GFR increased 50% and Li+ clearance doubled with both diets; in HK-alk versus HNa-LK, the increase in BP was less and ammoniagenesis was lower, abundance of proximal tubule transporters remained lower, ENaC-α fell, and NCCp increased, consistent with K+ conservation. After uninephrectomy, independent of diet, albuminuria increased eight-fold and abundance of endocytic receptors was reduced (megalin by 44%, disabled homolog 2 by 25%–35%) and kidney injury molecule-1 was increased. Conclusions The K-alkali–enriched diet blunted post-uninephrectomy hypertension and facilitated acid clearance by suppressing proximal Na+ transporters and increasing K+-alkali secretion. Furthermore, uninephrectomy-associated proteinuria could be attributed, at least in part, to elevated single-nephron GFR coupled with downregulation of megalin, which reduced fractional protein endocytosis and Vmax. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_07_31_ASN0000000000000420.mp3
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Affiliation(s)
- Donna L. Ralph
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Darren Ha
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Hillmin Lei
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Taylor S. Priver
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Scotti D. Smith
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Brandon E. McFarlin
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Seth Schwindt
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Drishti Pandya
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Hermann Koepsell
- Institute for Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany
| | - Nuria M. Pastor-Soler
- Division of Nephrology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Aurelie Edwards
- Department of Biomedical Engineering, Boston University, Boston, Massachusetts
| | - Alicia A. McDonough
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California
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Drury ER, Wu J, Gigliotti JC, Le TH. Sex differences in blood pressure regulation and hypertension: renal, hemodynamic, and hormonal mechanisms. Physiol Rev 2024; 104:199-251. [PMID: 37477622 PMCID: PMC11281816 DOI: 10.1152/physrev.00041.2022] [Citation(s) in RCA: 31] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 06/06/2023] [Accepted: 07/16/2023] [Indexed: 07/22/2023] Open
Abstract
The teleology of sex differences has been argued since at least as early as Aristotle's controversial Generation of Animals more than 300 years BC, which reflects the sex bias of the time to contemporary readers. Although the question "why are the sexes different" remains a topic of debate in the present day in metaphysics, the recent emphasis on sex comparison in research studies has led to the question "how are the sexes different" being addressed in health science through numerous observational studies in both health and disease susceptibility, including blood pressure regulation and hypertension. These efforts have resulted in better understanding of differences in males and females at the molecular level that partially explain their differences in vascular function and renal sodium handling and hence blood pressure and the consequential cardiovascular and kidney disease risks in hypertension. This review focuses on clinical studies comparing differences between men and women in blood pressure over the life span and response to dietary sodium and highlights experimental models investigating sexual dimorphism in the renin-angiotensin-aldosterone, vascular, sympathetic nervous, and immune systems, endothelin, the major renal sodium transporters/exchangers/channels, and the impact of sex hormones on these systems in blood pressure homeostasis. Understanding the mechanisms governing sex differences in blood pressure regulation could guide novel therapeutic approaches in a sex-specific manner to lower cardiovascular risks in hypertension and advance personalized medicine.
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Affiliation(s)
- Erika R Drury
- Division of Nephrology, Department of Medicine, University of Rochester Medical Center, Rochester, New York, United States
| | - Jing Wu
- Division of Nephrology, Department of Medicine, University of Rochester Medical Center, Rochester, New York, United States
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, United States
| | - Joseph C Gigliotti
- Department of Integrative Physiology and Pharmacology, Liberty University College of Osteopathic Medicine, Lynchburg, Virginia, United States
| | - Thu H Le
- Division of Nephrology, Department of Medicine, University of Rochester Medical Center, Rochester, New York, United States
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McDonough AA, Harris AN, Xiong LI, Layton AT. Sex differences in renal transporters: assessment and functional consequences. Nat Rev Nephrol 2024; 20:21-36. [PMID: 37684523 PMCID: PMC11090267 DOI: 10.1038/s41581-023-00757-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2023] [Indexed: 09/10/2023]
Abstract
Mammalian kidneys are specialized to maintain fluid and electrolyte homeostasis. The epithelial transport processes along the renal tubule that match output to input have long been the subject of experimental and theoretical study. However, emerging data have identified a new dimension of investigation: sex. Like most tissues, the structure and function of the kidney is regulated by sex hormones and chromosomes. Available data demonstrate sex differences in the abundance of kidney solute and electrolyte transporters, establishing that renal tubular organization and operation are distinctly different in females and males. Newer studies have provided insights into the physiological consequences of these sex differences. Computational simulations predict that sex differences in transporter abundance are likely driven to optimize reproduction, enabling adaptive responses to the nutritional requirements of serial pregnancies and lactation - normal life-cycle changes that challenge the ability of renal transporters to maintain fluid and electrolyte homeostasis. Later in life, females may also undergo menopause, which is associated with changes in disease risk. Although numerous knowledge gaps remain, ongoing studies will provide further insights into the sex-specific mechanisms of sodium, potassium, acid-base and volume physiology throughout the life cycle, which may lead to therapeutic opportunities.
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Affiliation(s)
- Alicia A McDonough
- Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
| | - Autumn N Harris
- Department of Small Animal Clinical Sciences, University of Florida, College of Veterinary Medicine, Gainesville, FL, USA
| | - Lingyun Ivy Xiong
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Anita T Layton
- Departments of Applied Mathematics and Biology, University of Waterloo, Waterloo, Ontario, Canada
- Cheriton School of Computer Science, University of Waterloo, Waterloo, Ontario, Canada
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
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Edwards A, Ralph DL, Mercado A, McDonough AA. Angiotensin II hypertension along the female rat tubule: predicted impact on coupled transport of Na + and K . Am J Physiol Renal Physiol 2023;325:F733-F749. [PMID: 37823196 PMCID: PMC10878725 DOI: 10.1152/ajprenal.00232.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 10/05/2023] [Accepted: 10/05/2023] [Indexed: 10/13/2023] Open
Abstract
Chronic infusion of subpressor level of angiotensin II (ANG II) increases the abundance of Na+ transporters along the distal nephron, balanced by suppression of Na+ transporters along the proximal tubule and medullary thick ascending limb (defined as "proximal nephron"), which impacts K+ handling along the entire renal tubule. The objective of this study was to quantitatively assess the impact of chronic ANG II on the renal handling of Na+ and K+ in female rats, using a computational model of the female rat renal tubule. Our results indicate that the downregulation of proximal nephron Na+ reabsorption (TNa), which occurs in response to ANG II-triggered hypertension, involves changes in both transporter abundance and trafficking. Our model suggests that substantial (∼30%) downregulation of active NHE3 in proximal tubule (PT) microvilli is needed to reestablish the Na+ balance at 2 wk of ANG II infusion. The 35% decrease in SGLT2, a known NHE3 regulator, may contribute to this downregulation. Both depression of proximal nephron TNa and stimulation of distal ENaC raise urinary K+ excretion in ANG II-treated females, while K+ loss is slightly mitigated by cortical NKCC2 and NCC upregulation. Our model predicts that K+ excretion may be more significantly limited during ANG II infusion by ROMK inhibition in the distal nephron and/or KCC3 upregulation in the PT, which remain open questions for experimental validation. In summary, our analysis indicates that ANG II hypertension triggers a series of events from distal TNa stimulation followed by compensatory reduction in proximal nephron TNa and accompanying adjustments to limit excessive K+ secretion.NEW & NOTEWORTHY We used a computational model of the renal tubule to assess the impact of 2-wk angiotensin II (ANG II) infusion on the handling of Na+ and K+ in female rats. ANG II strongly stimulates distal Na+ reabsorption and K+ secretion. Simulations indicate that substantial downregulation of proximal tubule NHE3 is needed to reestablish Na+ balance at 2 wk. Proximal adaptations challenge K+ homeostasis, and regulation of distal NCC and specific K+ channels likely limit urinary K+ losses.
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Affiliation(s)
- Aurélie Edwards
- Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States
| | - Donna L Ralph
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California, United States
| | - Adriana Mercado
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Alicia A McDonough
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California, United States
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Latt KZ, Yoshida T, Shrivastav S, Abedini A, Reece JM, Sun Z, Lee H, Okamoto K, Dagur P, Heymann J, Zhao Y, Chung JY, Hewitt S, Jose PA, Lee K, He JC, Winkler CA, Knepper MA, Kino T, Rosenberg AZ, Susztak K, Kopp JB. HIV viral protein R induces loss of DCT1-type renal tubules. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.02.526686. [PMID: 36945458 PMCID: PMC10028744 DOI: 10.1101/2023.02.02.526686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hyponatremia and salt wasting is a common occurance in patients with HIV/AIDS, however, the understanding of its contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the expression level of the Slc12a3 gene, encoding the Na-Cl cotransporter, which is responsible for sodium reabsorption in distal nephron segments, we performed single-nucleus RNA sequencing of kidney cortices from three wild-type (WT) and three Vpr-transgenic (Vpr Tg) mice. The results showed that the percentage of distal convoluted tubule (DCT) cells was significantly lower in Vpr Tg mice compared with WT mice (P < 0.05), and that in Vpr Tg mice, Slc12a3 expression was not different in DCT cell cluster. The Pvalb+ DCT1 subcluster had fewer cells in Vpr Tg mice compared with WT (P < 0.01). Immunohistochemistry demonstrated fewer Slc12a3+ Pvalb+ DCT1 segments in Vpr Tg mice. Differential gene expression analysis comparing Vpr Tg and WT in the DCT cluster showed Ier3, an inhibitor of apoptosis, to be the most downregulated gene. These observations demonstrate that the salt-wasting effect of Vpr in Vpr Tg mice is mediated by loss of Slc12a3+ Pvalb+ DCT1 segments via apoptosis dysregulation.
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Affiliation(s)
- Khun Zaw Latt
- Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda MD
| | - Teruhiko Yoshida
- Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda MD
| | - Shashi Shrivastav
- Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda MD
| | - Amin Abedini
- Department of Medicine, Renal Electrolyte and Hypertension Division; Institute for Diabetes, Obesity, and Metabolism; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Jeff M. Reece
- Advanced Light Microscopy & Image Analysis Core (ALMIAC), NIDDK, NIH, Bethesda, MD
| | - Zeguo Sun
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Hewang Lee
- Departments of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC
| | - Koji Okamoto
- Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda MD
- Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University Hospital, Aoba-ku, Sendai, Miyagi, Japan
| | - Pradeep Dagur
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Jurgen Heymann
- Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda MD
| | - Yongmei Zhao
- Advanced Biomedical and Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., NCI, Frederick, MD
| | - Joon-Yong Chung
- Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD
| | - Stephen Hewitt
- Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD
| | - Pedro A. Jose
- Departments of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC
- Departments of Physiology and Pharmacology, The George Washington University School of Medicine & Health Sciences, Washington, DC
| | - Kyung Lee
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - John Cijiang He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Cheryl A. Winkler
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute and Basic Research Program, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Mark A. Knepper
- Epithelial Systems Biology Laboratory, Systems Biology Center, Division of Intramural Research, NHLBI, NIH, Bethesda, MD
| | - Tomoshige Kino
- Laboratory for Molecular and Genomic Endocrinology, Division of Translational Medicine, Sidra Medicine, Doha, Qatar
| | - Avi Z. Rosenberg
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Katalin Susztak
- Department of Medicine, Renal Electrolyte and Hypertension Division; Institute for Diabetes, Obesity, and Metabolism; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Jeffrey B. Kopp
- Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda MD
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9
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Goto S, Yoshida Y, Hosojima M, Kuwahara S, Kabasawa H, Aoki H, Iida T, Sawada R, Ugamura D, Yoshizawa Y, Takemoto K, Komochi K, Kobayashi R, Kaseda R, Yaoita E, Nagatoishi S, Narita I, Tsumoto K, Saito A. Megalin is involved in angiotensinogen-induced, angiotensin II-mediated ERK1/2 signaling to activate Na + -H + exchanger 3 in proximal tubules. J Hypertens 2023; 41:1831-1843. [PMID: 37682076 DOI: 10.1097/hjh.0000000000003555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/09/2023]
Abstract
BACKGROUND Kidney angiotensin (Ang) II is produced mainly from liver-derived, glomerular-filtered angiotensinogen (AGT). Podocyte injury has been reported to increase the kidney Ang II content and induce Na + retention depending on the function of megalin, a proximal tubular endocytosis receptor. However, how megalin regulates the renal content and action of Ang II remains elusive. METHODS We used a mass spectrometry-based, parallel reaction-monitoring assay to quantitate Ang II in plasma, urine, and kidney homogenate of kidney-specific conditional megalin knockout (MegKO) and control (Ctl) mice. We also evaluated the pathophysiological changes in both mouse genotypes under the basal condition and under the condition of increased glomerular filtration of AGT induced by administration of recombinant mouse AGT (rec-mAGT). RESULTS Under the basal condition, plasma and kidney Ang II levels were comparable in the two mouse groups. Ang II was detected abundantly in fresh spot urine in conditional MegKO mice. Megalin was also found to mediate the uptake of intravenously administered fluorescent Ang II by PTECs. Administration of rec-mAGT increased kidney Ang II, exerted renal extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, activated proximal tubular Na + -H + exchanger 3 (NHE3), and decreased urinary Na + excretion in Ctl mice, whereas these changes were suppressed but urinary Ang II was increased in conditional MegKO mice. CONCLUSION Increased glomerular filtration of AGT is likely to augment Ang II production in the proximal tubular lumen. Thus, megalin-dependent Ang II uptake should be involved in the ERK1/2 signaling that activates proximal tubular NHE3 in vivo , thereby causing Na + retention.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Ryohei Kaseda
- Department of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata
| | | | | | - Ichiei Narita
- Department of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata
| | - Kouhei Tsumoto
- The Institute of Medical Science and Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
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Gamba G. Thirty years of the NaCl cotransporter: from cloning to physiology and structure. Am J Physiol Renal Physiol 2023; 325:F479-F490. [PMID: 37560773 PMCID: PMC10639029 DOI: 10.1152/ajprenal.00114.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/08/2023] [Accepted: 08/08/2023] [Indexed: 08/11/2023] Open
Abstract
The primary structure of the thiazide-sensitive NaCl cotransporter (NCC) was resolved 30 years ago by the molecular identification of the cDNA encoding this cotransporter, from the winter's flounder urinary bladder, following a functional expression strategy. This review outlines some aspects of how the knowledge about thiazide diuretics and NCC evolved, the history of the cloning process, and the expansion of the SLC12 family of electroneutral cotransporters. The diseases associated with activation or inactivation of NCC are discussed, as well as the molecular model by which the activity of NCC is regulated. The controversies in the field are discussed as well as recent publication of the three-dimensional model of NCC obtained by cryo-electron microscopy, revealing not only the amino acid residues critical for Na+ and Cl- translocation but also the residues critical for polythiazide binding to the transporter, opening the possibility for a new era in thiazide diuretic therapy.
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Affiliation(s)
- Gerardo Gamba
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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11
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Copur S, Peltek IB, Mutlu A, Tanriover C, Kanbay M. A new immune disease: systemic hypertension. Clin Kidney J 2023; 16:1403-1419. [PMID: 37664577 PMCID: PMC10469084 DOI: 10.1093/ckj/sfad059] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Indexed: 09/05/2023] Open
Abstract
Systemic hypertension is the most common medical comorbidity affecting the adult population globally, with multiple associated outcomes including cerebrovascular diseases, cardiovascular diseases, vascular calcification, chronic kidney disease, metabolic syndrome and mortality. Despite advancements in the therapeutic field approximately one in every five adult patients with hypertension is classified as having treatment-resistant hypertension, indicating the need for studies to provide better understanding of the underlying pathophysiology and the need for more therapeutic targets. Recent pre-clinical studies have demonstrated the role of the innate and adaptive immune system including various cell types and cytokines in the pathophysiology of hypertension. Moreover, pre-clinical studies have indicated the potential beneficial effects of immunosuppressant medications in the control of hypertension. Nevertheless, it is unclear whether such pathophysiological mechanisms and therapeutic alternatives are applicable to human subjects, while this area of research is undoubtedly a rapidly growing field.
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Affiliation(s)
- Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Ibrahim B Peltek
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Ali Mutlu
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Cem Tanriover
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Mehmet Kanbay
- Department of Medicine, Section of Nephrology, Koc University School of Medicine, Istanbul, Turkey
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12
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Modi AD, Khan AN, Cheng WYE, Modi DM. KCCs, NKCCs, and NCC: Potential targets for cardiovascular therapeutics? A comprehensive review of cell and region specific expression and function. Acta Histochem 2023; 125:152045. [PMID: 37201245 DOI: 10.1016/j.acthis.2023.152045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 05/11/2023] [Accepted: 05/12/2023] [Indexed: 05/20/2023]
Abstract
Cardiovascular diseases, the leading life-threatening conditions, involve cardiac arrhythmia, coronary artery disease, myocardial infarction, heart failure, cardiomyopathy, and heart valve disease that are associated with the altered functioning of cation-chloride cotransporters. The decreased number of cation-chloride cotransporters leads to reduced reactivity to adrenergic stimulation. The KCC family is crucial for numerous physiological processes including cell proliferation and invasion, regulation of membrane trafficking, maintaining ionic and osmotic homeostasis, erythrocyte swelling, dendritic spine formation, maturation of postsynaptic GABAergic inhibition, and inhibitory/excitatory signaling in neural tracts. KCC2 maintains intracellular chlorine homeostasis and opposes β-adrenergic stimulation-induced Cl- influx to prevent arrhythmogenesis. KCC3-inactivated cardiac tissue shows increased vascular resistance, aortic distensibility, heart size and weight (i.e. hypertrophic cardiomyopathy). Due to KCC4's high affinity for K+, it plays a vital role in cardiac ischemia with increased extracellular K+. The NKCC and NCC families play a vital role in the regulation of saliva volume, establishing the potassium-rich endolymph in the cochlea, sodium uptake in astrocytes, inhibiting myogenic response in microcirculatory beds, regulation of smooth muscle tone in resistance vessels, and blood pressure. NKCC1 regulates chlorine homeostasis and knocking it out impairs cardiomyocyte depolarization and cardiac contractility as well as impairs depolarization and contractility of vascular smooth muscle rings in the aorta. The activation of NCC in vascular cells promotes the formation of the abdominal aortic aneurysm. This narrative review provides a deep insight into the structure and function of KCCs, NKCCs, and NCC in human physiology and cardiac pathobiology. Also, it provides cell-specific (21 cell types) and region-specific (6 regions) expression of KCC1, KCC2, KCC3, KCC4, NKCC1, NKCC2, and NCC in heart.
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Affiliation(s)
- Akshat D Modi
- Department of Biological Sciences, University of Toronto, Scarborough, Ontario M1C 1A4, Canada; Department of Genetics and Development, Krembil Research Institute, Toronto, Ontario M5T 0S8, Canada.
| | - Areej Naim Khan
- Department of Human Biology, University of Toronto, Toronto, Ontario M5S 3J6, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Wing Yan Elizabeth Cheng
- Department of Neuroscience, University of Toronto, Scarborough, Ontario M1C 1A4, Canada; Department of Biochemistry, University of Toronto, Scarborough, Ontario M1C 1A4, Canada
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13
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Stevenson MD, Vendrov AE, Yang X, Chen Y, Navarro HA, Moss N, Runge MS, Arendshorst WJ, Madamanchi NR. Reactivity of renal and mesenteric resistance vessels to angiotensin II is mediated by NOXA1/NOX1 and superoxide signaling. Am J Physiol Renal Physiol 2023; 324:F335-F352. [PMID: 36759130 PMCID: PMC10026993 DOI: 10.1152/ajprenal.00236.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 01/17/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
Activation of NADPH oxidase (NOX) enzymes and the generation of reactive oxygen species and oxidative stress regulate vascular and renal function and contribute to the pathogenesis of hypertension. The present study examined the role of NOXA1/NOX1 function in vascular reactivity of renal and mesenteric resistance arteries/arterioles of wild-type and Noxa1-/- mice. A major finding was that renal blood flow is less sensitive to acute stimulation by angiotensin II (ANG II) in Noxa1-/- mice compared with wild-type mice, with a direct action on resistance arterioles independent of nitric oxide (NO) bioavailability. These functional results were reinforced by immunofluorescence evidence of NOXA1/NOX1 protein presence in renal arteries, afferent arterioles, and glomeruli as well as their upregulation by ANG II. In contrast, the renal vascular response to the thromboxane mimetic U46619 was effectively blunted by NO and was similar in both mouse genotypes and thus independent of NOXA1/NOX1 signaling. However, phenylephrine- and ANG II-induced contraction of isolated mesenteric arteries was less pronounced and buffering of vasoconstriction after acetylcholine and nitroprusside stimulation was reduced in Noxa1-/- mice, suggesting endothelial NO-dependent mechanisms. An involvement of NOXA1/NOX1/O2•- signaling in response to ANG II was demonstrated with the specific NOXA1/NOX1 assembly inhibitor C25 and the nonspecific NOX inhibitor diphenyleneiodonium chloride in cultured vascular smooth muscle cells and isolated mesenteric resistance arteries. Collectively, our data indicate that the NOX1/NOXA1/O2•- pathway contributes to acute vasoconstriction induced by ANG II in renal and mesenteric vascular beds and may contribute to ANG II-induced hypertension.NEW & NOTEWORTHY Renal reactivity to angiotensin II (ANG II) is mediated by superoxide signaling produced by NADPH oxidase (NOX)A1/NOX1. Acute vasoconstriction of renal arteries by ANG was blunted in Noxa1-/- compared with wild-type mice. NOXA1/NOX1/O2•- signaling was also observed in ANG II stimulation of vascular smooth muscle cells and isolated mesenteric resistance arteries, indicating that it contributes to ANG II-induced hypertension. A NOXA1/NOX1 assembly inhibitor (C25) has been characterized that inhibits superoxide production and ameliorates the effects of ANG II.
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Affiliation(s)
- Mark D Stevenson
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
| | - Aleksandr E Vendrov
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
| | - Xi Yang
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, United States
| | - Yuenmu Chen
- McAllister Heart Institute, Division of Cardiology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States
| | - Hernán A Navarro
- Center for Drug Discovery, Organic and Medicinal Chemistry, RTI International, Research Triangle Park, North Carolina, United States
| | - Nicholas Moss
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, United States
| | - Marschall S Runge
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
| | - William J Arendshorst
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, United States
| | - Nageswara R Madamanchi
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
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14
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Intrarenal neurohormonal modulation by renal denervation: benefits for chronic kidney disease and heart failure. Hypertens Res 2023; 46:518-520. [PMID: 36400846 DOI: 10.1038/s41440-022-01104-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/31/2022] [Accepted: 11/01/2022] [Indexed: 11/19/2022]
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15
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Meister ML, Najjar RS, Danh JP, Knapp D, Wanders D, Feresin RG. Berry consumption mitigates the hypertensive effects of a high-fat, high-sucrose diet via attenuation of renal and aortic AT 1R expression resulting in improved endothelium-derived NO bioavailability. J Nutr Biochem 2023; 112:109225. [PMID: 36435288 DOI: 10.1016/j.jnutbio.2022.109225] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 10/12/2022] [Accepted: 11/17/2022] [Indexed: 11/25/2022]
Abstract
Dysregulation of the renin-angiotensin system (RAS) is a contributor to high-fat diet-related blood pressure (BP) increases. Deleterious effects of dysregulated RAS result in an overproduction of reactive oxygen species and a decrease in endothelial nitric oxide (NO) bioavailability due to increased NADPH oxidase (NOX) expression. Dietary polyphenols have been shown to mitigate the imbalance in the redox state and protect against endothelial dysfunction induced by a high-fat diet. Thus, we aim to determine whether polyphenol-rich blackberry and raspberry, alone and in combination, attenuate the detrimental effects of a high-fat, high-sucrose (HFHS) diet on the vascular endothelium and kidneys of mice. We show that a HFHS diet increased the expression of renal and aortic angiotensin type 1 receptor (AT1R). Further, NOX1 and NOX4 expression were increased in the kidney contributing to fibrotic damage. In human aortic endothelial cells (HAECs), palmitic acid increased the expression of NOX4, potentially driving oxidative damage in the aorta, as evidenced by increased nitrotyrosine expression. Berries reduced the expression of renal and aortic AT1R, leading to a subsequent decrease in renal NOX expression and reduced aortic oxidative stress evidenced by reduced nitrotyrosine expression. Blackberry and raspberry in combination increased the expression of NRF2 and its downstream proteins in HAECs, thereby reducing the oxidative burden to the endothelium. In combination, blackberry and raspberry also increased serum levels of NO metabolites. These findings indicate that blackberry and raspberry unique polyphenols may act synergistically to favorably modulate the abovementioned pathways and attenuate HFHS diet-induced increases in BP.
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Affiliation(s)
- Maureen L Meister
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA
| | - Rami S Najjar
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA
| | - Jessica P Danh
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA
| | - Denise Knapp
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA
| | - Desiree Wanders
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA
| | - Rafaela G Feresin
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA.
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16
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Lai Y, Zhou H, Chen W, Liu H, Liu G, Xu Y, Du H, Zhang B, Li Y, Woo K, Yin Y. The intrarenal blood pressure modulation system is differentially altered after renal denervation guided by different intensities of blood pressure responses. Hypertens Res 2023; 46:456-467. [PMID: 36202981 DOI: 10.1038/s41440-022-01047-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 02/07/2023]
Abstract
The aim of this study was to investigate alterations in the intrarenal blood pressure (BP) regulation system after renal denervation (RDN) guided by renal nerve stimulation (RNS). Twenty-one dogs were randomized to receive RDN at strong (SRA group, n = 7) or weak (WRA group, n = 7) BP-elevation response sites identified by RNS or underwent RNS only (RNS-control, RSC, n = 7). After 4 weeks of follow-up, renal sympathetic components, the main components of renin-angiotensin system (RAS) and the major transporters involved in sodium and water reabsorption were assessed by immunohistochemical analysis. Compared with RSC treatment, RDN therapy significantly reduced renal norepinephrine and tyrosine hydroxylase levels, decreased the renin content and inhibited the onsite generation of angiotensinogen. Moreover, the expression of exciting axis components, including angiotensin-converting enzyme (ACE), angiotensin II and angiotensin II type-1 receptor, was downregulated, while protective axis components for the cardiovascular system, including ACE2 and Mas receptors, were upregulated in both WRA and SRA groups. Moreover, RDN reduced the abundance of aquaporin-1 and aquaporin-2 in kidneys. Although RDN had a minimal effect on overall NKCC2 expression, its activation (p-NKCC2) and directional enrichment in the apical membrane (mNKCC2) were dramatically blunted. All these changes were more obvious in the SRA group than WRA group. Selective RDN guided by RNS effectively reduced systemic BP by affecting the renal neurohormone system, as well as the sodium and water transporter system, and these effects at sites with a strong BP response were more superior.
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Affiliation(s)
- Yinchuan Lai
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmia Therapeutic Service Center, Chongqing Key Laboratory of Arrhythmia, Chongqing, China
- Department of Cardiology, the Second People's Hospital of Yibin & West China Hospital, Sichuan University Yibin Hospital, Yibin City, Sichuan, China
| | - Hao Zhou
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmia Therapeutic Service Center, Chongqing Key Laboratory of Arrhythmia, Chongqing, China
| | - Weijie Chen
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmia Therapeutic Service Center, Chongqing Key Laboratory of Arrhythmia, Chongqing, China
| | - Hang Liu
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmia Therapeutic Service Center, Chongqing Key Laboratory of Arrhythmia, Chongqing, China
| | - Guangliang Liu
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmia Therapeutic Service Center, Chongqing Key Laboratory of Arrhythmia, Chongqing, China
| | - Yanping Xu
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmia Therapeutic Service Center, Chongqing Key Laboratory of Arrhythmia, Chongqing, China
| | - Huaan Du
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmia Therapeutic Service Center, Chongqing Key Laboratory of Arrhythmia, Chongqing, China
| | - Bo Zhang
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmia Therapeutic Service Center, Chongqing Key Laboratory of Arrhythmia, Chongqing, China
| | - Yidan Li
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmia Therapeutic Service Center, Chongqing Key Laboratory of Arrhythmia, Chongqing, China
| | - Kamsang Woo
- Institute of Future Cities, the Chinese University of Hong Kong, Hong Kong, China
| | - Yuehui Yin
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmia Therapeutic Service Center, Chongqing Key Laboratory of Arrhythmia, Chongqing, China.
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17
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Uchida S, Mori T, Susa K, Sohara E. NCC regulation by WNK signal cascade. Front Physiol 2023; 13:1081261. [PMID: 36685207 PMCID: PMC9845728 DOI: 10.3389/fphys.2022.1081261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/14/2022] [Indexed: 01/06/2023] Open
Abstract
With-no-lysine (K) (WNK) kinases have been identified as the causal genes for pseudohypoaldosteronism type II (PHAII), a rare hereditary hypertension condition characterized by hyperkalemia, hyperchloremic metabolic acidosis, and thiazide-hypersensitivity. We thought that clarifying the link between WNK and NaCl cotransporter (NCC) would bring us new mechanism(s) of NCC regulation. For the first time, we were able to produce a knock-in mouse model of PHAII and anti-phosphorylated NCC antibodies against the putative NCC phosphorylation sites and discover that constitutive activation of NCC and increased phosphorylation of NCC are the primary pathogenesis of the disease in vivo. We have since demonstrated that this regulatory mechanism is mediated by the kinases oxidative stress-response protein 1 (OSR1) and STE20/SPS1-related proline/alanine-rich kinase (SPAK) (WNK-OSR1/SPAK-NCC signaling cascade) and that the signaling is not only important in the pathological condition of PHAII but also plays a crucial physiological role in the regulation of NCC.
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18
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Renal angiotensin I-converting enzyme-deficient mice are protected against aristolochic acid nephropathy. Pflugers Arch 2023; 475:391-403. [PMID: 36520238 PMCID: PMC9908662 DOI: 10.1007/s00424-022-02779-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/30/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022]
Abstract
The renal renin-angiotensin system (RAS) is involved in the development of chronic kidney disease. Here, we investigated whether mice with reduced renal angiotensin I-converting enzyme (ACE-/-) are protected against aristolochic acid nephropathy (AAN). To further elucidate potential molecular mechanisms, we assessed the renal abundances of several major RAS components. AAN was induced using aristolochic acid I (AAI). Glomerular filtration rate (GFR) was determined using inulin clearance and renal protein abundances of renin, angiotensinogen, angiotensin I-converting enzyme (ACE) 2, and Mas receptor (Mas) were determined in ACE-/- and C57BL/6J control mice by Western blot analyses. Renal ACE activity was determined using a colorimetric assay and renal angiotensin (Ang) (1-7) concentration was determined by ELISA. GFR was similar in vehicle-treated mice of both strains. AAI decreased GFR in controls but not in ACE-/- mice. Furthermore, AAI decreased renal ACE activity in controls but not in ACE-/- mice. Vehicle-treated ACE-/- mice had significantly higher renal ACE2 and Mas protein abundances than controls. AAI decreased renal ACE2 protein abundance in both strains. Furthermore, AAI increased renal Mas protein abundance, although the latter effect did not reach statistical significance in the ACE-/- mice. Renal Ang(1-7) concentration was similar in vehicle-treated mice of both strains. AAI increased renal Ang(1-7) concentration in the ACE-/- mice but not in the controls. Mice with reduced renal ACE are protected against AAN. Our data suggest that in the face of renal ACE deficiency, AAI may activate the ACE2/Ang(1-7)/Mas axis, which in turn may deploy its reno-protective effects.
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Lin H, Geurts F, Hassler L, Batlle D, Mirabito Colafella KM, Denton KM, Zhuo JL, Li XC, Ramkumar N, Koizumi M, Matsusaka T, Nishiyama A, Hoogduijn MJ, Hoorn EJ, Danser AHJ. Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting. Pharmacol Rev 2022; 74:462-505. [PMID: 35710133 PMCID: PMC9553117 DOI: 10.1124/pharmrev.120.000236] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. SIGNIFICANCE STATEMENT: Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.
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Affiliation(s)
- Hui Lin
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Frank Geurts
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Luise Hassler
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Daniel Batlle
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Katrina M Mirabito Colafella
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Kate M Denton
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Jia L Zhuo
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Xiao C Li
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Nirupama Ramkumar
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Masahiro Koizumi
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Taiji Matsusaka
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Akira Nishiyama
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Martin J Hoogduijn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Ewout J Hoorn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - A H Jan Danser
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
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20
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Khundmiri SJ, Ecelbarger CM, Amponsem J, Ji H, Sandberg K, Lee DL. PPAR-α knockout leads to elevated blood pressure response to angiotensin II infusion associated with an increase in renal α-1 Na +/K + ATPase protein expression and activity. Life Sci 2022; 296:120444. [PMID: 35245523 PMCID: PMC8969884 DOI: 10.1016/j.lfs.2022.120444] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 02/15/2022] [Accepted: 02/26/2022] [Indexed: 01/13/2023]
Abstract
Peroxisome proliferator activated receptor alpha (PPAR-α) deletion has been shown to increase blood pressure (BP). We hypothesized that the BP increase in PPAR-α KO mice was mediated by increased expression and activity of basolateral Na+/K+ ATPase (NKA) pump. To address this hypothesis, we treated wild-type (WT) and PPAR-α knockout (KO) mice with a slow-pressor dose of angiotensin II (400 ng/kg·min) for 12 days by osmotic minipump. Radiotelemetry showed no significant differences in baseline mean arterial pressure (MAP) between WT and PPAR-α KO mice; however, by day 12 of infusion, MAP was significantly higher in PPAR-α KO mice (156 ± 16) compared to WT mice (138 ± 11 mmHg). NKA activity and protein expression (α1 subunit) were significantly higher in PPAR-α KO mice compared to WT mice. There was no significant difference in NKA mRNA levels. Angiotensin II further increased the expression and activity of the NKA in both genotypes along with the water channel, aquaporin 1 (Aqp1). In contrast, angiotensin II decreased the expression (64-97% reduction in band density) of sodium‑hydrogen exchanger-3 (NHE3), NHE regulatory factor-1 (NHERF1, Slc9a3r1), sodium‑potassium-2-chloride cotransporter (NKCC2), and epithelial sodium channel (ENaC) β- and γ- subunits in the renal cortex of both WT and PPAR-α KO mice, with no difference between genotypes. The sodium-chloride cotransporter (NCC) was also decreased by angiotensin II, but significantly more in PPAR-α KO (59% WT versus 77% KO reduction from their respective vehicle-treated mice). Our results suggest that PPAR-α attenuates angiotensin II-mediated increased blood pressure potentially via reducing expression and activity of the NKA.
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Affiliation(s)
- Syed J Khundmiri
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, USA.
| | - Carolyn M Ecelbarger
- Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University Washington, DC, USA
| | - Joycemary Amponsem
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, USA
| | - Hong Ji
- Department of Medicine, Georgetown University Washington, DC, USA
| | - Kathryn Sandberg
- Department of Medicine, Georgetown University Washington, DC, USA
| | - Dexter L Lee
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, USA.
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21
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Vendrov AE, Stevenson MD, Lozhkin A, Hayami T, Holland NA, Yang X, Moss N, Pan H, Wickline SA, Stockand JD, Runge MS, Madamanchi NR, Arendshorst WJ. Renal NOXA1/NOX1 Signaling Regulates Epithelial Sodium Channel and Sodium Retention in Angiotensin II-induced Hypertension. Antioxid Redox Signal 2022; 36:550-566. [PMID: 34714114 PMCID: PMC8978567 DOI: 10.1089/ars.2021.0047] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Aims: NADPH oxidase (NOX)-derived reactive oxygen species (ROS) are implicated in the pathophysiology of hypertension in chronic kidney disease patients. Genetic deletion of NOX activator 1 (Noxa1) subunit of NOX1 decreases ROS under pathophysiological conditions. Here, we investigated the role of NOXA1-dependent NOX1 activity in the pathogenesis of angiotensin II (Ang II)-induced hypertension (AIH) and possible involvement of abnormal renal function. Results: NOXA1 is present in epithelial cells of Henle's thick ascending limb and distal nephron. Telemetry showed lower basal systolic blood pressure (BP) in Noxa1-/-versus wild-type mice. Ang II infusion for 1 and 14 days increased NOXA1/NOX1 expression and ROS in kidney of male but not female wild-type mice. Mean BP increased 30 mmHg in wild-type males, with smaller increases in Noxa1-deficient males and wild-type or Noxa1-/- females. In response to an acute salt load, Na+ excretion was similar in wild-type and Noxa1-/- mice before and 14 days after Ang II infusion. However, Na+ excretion was delayed after 1-2 days of Ang II in male wild-type versus Noxa1-/- mice. Ang II increased epithelial Na+ channel (ENaC) levels and activation in the collecting duct principal epithelial cells of wild-type but not Noxa1-/- mice. Aldosterone induced ROS levels and Noxa1 and Scnn1a expression and ENaC activity in a mouse renal epithelial cell line, responses abolished by Noxa1 small-interfering RNA. Innovation and Conclusion: Ang II activation of renal NOXA1/NOX1-dependent ROS enhances tubular ENaC expression and Na+ reabsorption, leading to increased BP. Attenuation of AIH in females is attributed to weaker NOXA1/NOX1-dependent ROS signaling and efficient natriuresis. Antioxid. Redox Signal. 36, 550-566.
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Affiliation(s)
- Aleksandr E Vendrov
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Mark D Stevenson
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Andrey Lozhkin
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Takayuki Hayami
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Nathan A Holland
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Xi Yang
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Nicholas Moss
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Hua Pan
- Department of Cardiovascular Sciences, University of South Florida, Tampa, Florida, USA
| | - Samuel A Wickline
- Department of Cardiovascular Sciences, University of South Florida, Tampa, Florida, USA
| | - James D Stockand
- Department of Cellular and Integrative Physiology, University of Texas Health Science Centre at San Antonio, San Antonio, Texas, USA
| | - Marschall S Runge
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Nageswara R Madamanchi
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - William J Arendshorst
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, USA
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22
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Moser S, Sugano Y, Wengi A, Fisi V, Lindtoft Rosenbaek L, Mariniello M, Loffing‐Cueni D, McCormick JA, Fenton RA, Loffing J. A five amino acids deletion in NKCC2 of C57BL/6 mice affects analysis of NKCC2 phosphorylation but does not impact kidney function. Acta Physiol (Oxf) 2021; 233:e13705. [PMID: 34114742 PMCID: PMC8384713 DOI: 10.1111/apha.13705] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 05/04/2021] [Accepted: 06/07/2021] [Indexed: 12/24/2022]
Abstract
Aim The phosphorylation level of the furosemide‐sensitive Na+‐K+‐2Cl− cotransporter (NKCC2) in the thick ascending limb (TAL) is used as a surrogate marker for NKCC2 activation and TAL function. However, in mice, analyses of NKCC2 phosphorylation with antibodies against phosphorylated threonines 96 and 101 (anti‐pT96/pT101) give inconsistent results. We aimed (a) to elucidate these inconsistencies and (b) to develop a phosphoform‐specific antibody that ensures reliable detection of NKCC2 phosphorylation in mice. Methods Genetic information, molecular biology, biochemical techniques and mouse phenotyping was used to study NKCC2 and kidney function in two commonly used mouse strains (ie 129Sv and in C57BL/6 mice). Moreover, a new phosphoform‐specific mouse NKCC2 antibody was developed and characterized. Results Amino acids sequence alignment revealed that C57BL/6 mice have a strain‐specific five amino acids deletion (ΔF97‐T101) in NKCC2 that diminishes the detection of NKCC2 phosphorylation with previously developed pT96/pT101 NKCC2 antibodies. Instead, the antibodies cross‐react with the phosphorylated thiazide‐sensitive NaCl cotransporter (NCC), which can obscure interpretation of results. Interestingly, the deletion in NKCC2 does not impact on kidney function and/or expression of renal ion transport proteins as indicated by the analysis of the F2 generation of crossbred 129Sv and C57BL/6 mice. A newly developed pT96 NKCC2 antibody detects pNKCC2 in both mouse strains and shows no cross‐reactivity with phosphorylated NCC. Conclusion Our work reveals a hitherto unappreciated, but essential, strain difference in the amino acids sequence of mouse NKCC2 that needs to be considered when analysing NKCC2 phosphorylation in mice. The new pNKCC2 antibody circumvents this technical caveat.
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Affiliation(s)
- Sandra Moser
- Institute of Anatomy University of Zurich Zurich Switzerland
| | - Yuya Sugano
- Institute of Anatomy University of Zurich Zurich Switzerland
| | - Agnieszka Wengi
- Institute of Anatomy University of Zurich Zurich Switzerland
| | - Viktoria Fisi
- Institute of Anatomy University of Zurich Zurich Switzerland
| | | | | | | | - James A. McCormick
- Division of Nephrology and Hypertension Oregon Health & Science University Portland OR USA
| | | | - Johannes Loffing
- Institute of Anatomy University of Zurich Zurich Switzerland
- Swiss National Centre for Competence in Research “Kidney control of homeostasis” Zurich Switzerland
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23
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Wang F, Chen Y, Zou CJ, Luo R, Yang T. Mutagenesis of the Cleavage Site of Pro Renin Receptor Abrogates Angiotensin II-Induced Hypertension in Mice. Hypertension 2021; 78:115-127. [PMID: 34024121 PMCID: PMC9212214 DOI: 10.1161/hypertensionaha.121.16770] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
[Figure: see text].
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Affiliation(s)
- Fei Wang
- Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, USA
| | - Yanting Chen
- Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, USA
| | - Chang-jiang Zou
- Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, USA
| | - Renfei Luo
- Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, USA
| | - Tianxin Yang
- Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, USA
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24
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Giani JF, Veiras LC, Shen JZY, Bernstein EA, Cao D, Okwan-Duodu D, Khan Z, Gonzalez-Villalobos RA, Bernstein KE. Novel roles of the renal angiotensin-converting enzyme. Mol Cell Endocrinol 2021; 529:111257. [PMID: 33781839 PMCID: PMC8127398 DOI: 10.1016/j.mce.2021.111257] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 02/03/2021] [Accepted: 03/20/2021] [Indexed: 12/14/2022]
Abstract
The observation that all components of the renin angiotensin system (RAS) are expressed in the kidney and the fact that intratubular angiotensin (Ang) II levels greatly exceed the plasma concentration suggest that the synthesis of renal Ang II occurs independently of the circulating RAS. One of the main components of this so-called intrarenal RAS is angiotensin-converting enzyme (ACE). Although the role of ACE in renal disease is demonstrated by the therapeutic effectiveness of ACE inhibitors in treating several conditions, the exact contribution of intrarenal versus systemic ACE in renal disease remains unknown. Using genetically modified mouse models, our group demonstrated that renal ACE plays a key role in the development of several forms of hypertension. Specifically, although ACE is expressed in different cell types within the kidney, its expression in renal proximal tubular cells is essential for the development of high blood pressure. Besides hypertension, ACE is involved in several other renal diseases such as diabetic kidney disease, or acute kidney injury even when blood pressure is normal. In addition, studies suggest that ACE might mediate at least part of its effect through mechanisms that are independent of the Ang I conversion into Ang II and involve other substrates such as N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), Ang-(1-7), and bradykinin, among others. In this review, we summarize the recent advances in understanding the contribution of intrarenal ACE to different pathological conditions and provide insight into the many roles of ACE besides the well-known synthesis of Ang II.
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Affiliation(s)
- Jorge F Giani
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - Luciana C Veiras
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Justin Z Y Shen
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ellen A Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - DuoYao Cao
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Derick Okwan-Duodu
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Zakir Khan
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Kenneth E Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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25
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Emathinger JM, Nelson JW, Gurley SB. Advances in use of mouse models to study the renin-angiotensin system. Mol Cell Endocrinol 2021; 529:111255. [PMID: 33789143 PMCID: PMC9119406 DOI: 10.1016/j.mce.2021.111255] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 01/19/2021] [Accepted: 03/20/2021] [Indexed: 12/28/2022]
Abstract
The renin-angiotensin system (RAS) is a highly complex hormonal cascade that spans multiple organs and cell types to regulate solute and fluid balance along with cardiovascular function. Much of our current understanding of the functions of the RAS has emerged from a series of key studies in genetically-modified animals. Here, we review key findings from ground-breaking transgenic models, spanning decades of research into the RAS, with a focus on their use in studying blood pressure. We review the physiological importance of this regulatory system as evident through the examination of mouse models for several major RAS components: angiotensinogen, renin, ACE, ACE2, and the type 1 A angiotensin receptor. Both whole-animal and cell-specific knockout models have permitted critical RAS functions to be defined and demonstrate how redundancy and multiplicity within the RAS allow for compensatory adjustments to maintain homeostasis. Moreover, these models present exciting opportunities for continued discovery surrounding the role of the RAS in disease pathogenesis and treatment for cardiovascular disease and beyond.
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MESH Headings
- Angiotensin-Converting Enzyme 2/deficiency
- Angiotensin-Converting Enzyme 2/genetics
- Angiotensinogen/deficiency
- Angiotensinogen/genetics
- Animals
- Blood Pressure/genetics
- Cardiovascular Diseases/genetics
- Cardiovascular Diseases/metabolism
- Cardiovascular Diseases/pathology
- Disease Models, Animal
- Gene Expression Regulation
- Humans
- Kidney/cytology
- Kidney/metabolism
- Mice
- Mice, Knockout
- Receptor, Angiotensin, Type 1/deficiency
- Receptor, Angiotensin, Type 1/genetics
- Receptor, Angiotensin, Type 2/deficiency
- Receptor, Angiotensin, Type 2/genetics
- Renin/deficiency
- Renin/genetics
- Renin-Angiotensin System/genetics
- Signal Transduction
- Water-Electrolyte Balance/genetics
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Affiliation(s)
- Jacqueline M Emathinger
- Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR, USA.
| | - Jonathan W Nelson
- Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR, USA.
| | - Susan B Gurley
- Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR, USA.
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26
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Rianto F, Hoang T, Revoori R, Sparks MA. Angiotensin receptors in the kidney and vasculature in hypertension and kidney disease. Mol Cell Endocrinol 2021; 529:111259. [PMID: 33781840 DOI: 10.1016/j.mce.2021.111259] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 01/05/2021] [Accepted: 03/20/2021] [Indexed: 12/24/2022]
Abstract
Kidney disease, blood pressure determination, hypertension pathogenesis, and the renin-angiotensin system (RAS) are inextricably linked. Hence, understanding the RAS is pivotal to unraveling the pathophysiology of hypertension and the determinants to maintaining normal blood pressure. The RAS has been the subject of intense investigation for over a century. Moreover, medications that block the RAS are mainstay therapies in clinical medicine and have been shown to reduce morbidity and mortality in patients with diabetes, cardiovascular, and kidney diseases. The main effector peptide of the RAS is the interaction of the octapeptide- Ang II with its receptor. The type 1 angiotensin receptor (AT1R) is the effector receptor for Ang II. These G protein-coupled receptors (GPCRs) are ubiquitously expressed in a variety of cell lineages and tissues relevant to cardiovascular disease throughout the body. The advent of cell specific deletion of genes using Cre LoxP technology in mice has allowed for the identification of discreet actions of AT1Rs in blood pressure control and kidney disease. The kidney is one of the major targets of the RAS, which is responsible in maintaining fluid, electrolyte balance, and blood pressure. In this review we will discuss the role of AT1Rs in the kidney, vasculature, and immune cells and address their effects on hypertension and kidney disease.
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MESH Headings
- Angiotensin I/genetics
- Angiotensin I/metabolism
- Angiotensin II/genetics
- Angiotensin II/metabolism
- Angiotensin-Converting Enzyme 2/genetics
- Angiotensin-Converting Enzyme 2/metabolism
- Animals
- Blood Pressure/genetics
- Gene Expression Regulation
- Humans
- Hypertension/genetics
- Hypertension/metabolism
- Hypertension/pathology
- Kidney Tubules, Proximal/enzymology
- Kidney Tubules, Proximal/pathology
- Mice
- Mice, Knockout
- Peptide Fragments/genetics
- Peptide Fragments/metabolism
- Receptor, Angiotensin, Type 1/genetics
- Receptor, Angiotensin, Type 1/metabolism
- Receptor, Angiotensin, Type 2/genetics
- Receptor, Angiotensin, Type 2/metabolism
- Renal Insufficiency, Chronic/genetics
- Renal Insufficiency, Chronic/metabolism
- Renal Insufficiency, Chronic/pathology
- Renin-Angiotensin System/genetics
- Signal Transduction
- Water-Electrolyte Balance/genetics
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Affiliation(s)
- Fitra Rianto
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Thien Hoang
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Ritika Revoori
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Matthew A Sparks
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States; Renal Section, Durham VA Health Care System, Durham, NC, United States.
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27
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Sparks MA, Dilmen E, Ralph DL, Rianto F, Hoang TA, Hollis A, Diaz EJ, Adhikari R, Chew G, Petretto EG, Gurley SB, McDonough AA, Coffman TM. Vascular control of kidney epithelial transporters. Am J Physiol Renal Physiol 2021; 320:F1080-F1092. [PMID: 33969697 PMCID: PMC8285646 DOI: 10.1152/ajprenal.00084.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/23/2021] [Accepted: 05/05/2021] [Indexed: 01/03/2023] Open
Abstract
A major pathway in hypertension pathogenesis involves direct activation of ANG II type 1 (AT1) receptors in the kidney, stimulating Na+ reabsorption. AT1 receptors in tubular epithelia control expression and stimulation of Na+ transporters and channels. Recently, we found reduced blood pressure and enhanced natriuresis in mice with cell-specific deletion of AT1 receptors in smooth muscle (SMKO mice). Although impaired vasoconstriction and preserved renal blood flow might contribute to exaggerated urinary Na+ excretion in SMKO mice, we considered whether alterations in Na+ transporter expression might also play a role; therefore, we carried out proteomic analysis of key Na+ transporters and associated proteins. Here, we show that levels of Na+-K+-2Cl- cotransporter isoform 2 (NKCC2) and Na+/H+ exchanger isoform 3 (NHE3) are reduced at baseline in SMKO mice, accompanied by attenuated natriuretic and diuretic responses to furosemide. During ANG II hypertension, we found widespread remodeling of transporter expression in wild-type mice with significant increases in the levels of total NaCl cotransporter, phosphorylated NaCl cotransporter (Ser71), and phosphorylated NKCC2, along with the cleaved, activated forms of the α- and γ-epithelial Na+ channel. However, the increases in α- and γ-epithelial Na+ channel with ANG II were substantially attenuated in SMKO mice. This was accompanied by a reduced natriuretic response to amiloride. Thus, enhanced urinary Na+ excretion observed after cell-specific deletion of AT1 receptors from smooth muscle cells is associated with altered Na+ transporter abundance across epithelia in multiple nephron segments. These findings suggest a system of vascular-epithelial in the kidney, modulating the expression of Na+ transporters and contributing to the regulation of pressure natriuresis.NEW & NOTEWORTHY The use of drugs to block the renin-angiotensin system to reduce blood pressure is common. However, the precise mechanism for how these medications control blood pressure is incompletely understood. Here, we show that mice lacking angiotensin receptors specifically in smooth muscle cells lead to alternation in tubular transporter amount and function. Thus, demonstrating the importance of vascular-tubular cross talk in the control of blood pressure.
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Affiliation(s)
- Matthew A Sparks
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- Renal Section, Durham Veterans Affairs Health Care System, Durham, North Carolina
| | - Emre Dilmen
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Donna L Ralph
- Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Fitra Rianto
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Thien A Hoang
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Alison Hollis
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Edward J Diaz
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Rishav Adhikari
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Gabriel Chew
- Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore
| | - Enrico G Petretto
- Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore
| | - Susan B Gurley
- Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, Oregon
| | - Alicia A McDonough
- Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Thomas M Coffman
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- Renal Section, Durham Veterans Affairs Health Care System, Durham, North Carolina
- Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore
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28
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Veiras LC, Shen JZY, Bernstein EA, Regis GC, Cao D, Okwan-Duodu D, Khan Z, Gibb DR, Dominici FP, Bernstein KE, Giani JF. Renal Inflammation Induces Salt Sensitivity in Male db/db Mice through Dysregulation of ENaC. J Am Soc Nephrol 2021; 32:1131-1149. [PMID: 33731332 PMCID: PMC8259671 DOI: 10.1681/asn.2020081112] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 01/21/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Hypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown. METHODS Female and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension. RESULTS Male, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti-IL-6 antibody, prevented the development of salt sensitivity in male db/db mice. CONCLUSIONS The inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.
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Affiliation(s)
- Luciana C. Veiras
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Justin Z. Y. Shen
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Ellen A. Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Giovanna C. Regis
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - DuoYao Cao
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Derick Okwan-Duodu
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Zakir Khan
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - David R. Gibb
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Fernando P. Dominici
- Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
| | - Kenneth E. Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California,Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Jorge F. Giani
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California,Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
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29
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Shao S, Li XD, Lu YY, Li SJ, Chen XH, Zhou HD, He S, Guo YT, Lu X, Gao PJ, Wang JG. Renal Natriuretic Peptide Receptor-C Deficiency Attenuates NaCl Cotransporter Activity in Angiotensin II-Induced Hypertension. Hypertension 2021; 77:868-881. [PMID: 33486984 DOI: 10.1161/hypertensionaha.120.15636] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Genome-wide association studies have identified that NPR-C (natriuretic peptide receptor-C) variants are associated with elevation of blood pressure. However, the mechanism underlying the relationship between NPR-C and blood pressure regulation remains elusive. Here, we investigate whether NPR-C regulates Ang II (angiotensin II)-induced hypertension through sodium transporters activity. Wild-type mice responded to continuous Ang II infusion with an increased renal NPR-C expression. Global NPR-C deficiency attenuated Ang II-induced increased blood pressure both in male and female mice associated with more diuretic and natriuretic responses to a saline challenge. Interestingly, Ang II increased both total and phosphorylation of NCC (NaCl cotransporter) abundance involving in activation of WNK4 (with-no-lysine kinase 4)/SPAK (Ste20-related proline/alanine-rich kinase) which was blunted by NPR-C deletion. NCC inhibitor, hydrochlorothiazide, failed to induce natriuresis in NPR-C knockout mice. Moreover, low-salt and high-salt diets-induced changes of total and phosphorylation of NCC expression were normalized by NPR-C deletion. Importantly, tubule-specific deletion of NPR-C also attenuated Ang II-induced elevated blood pressure, total and phosphorylation of NCC expression. Mechanistically, in distal convoluted tubule cells, Ang II dose and time-dependently upregulated WNK4/SPAK/NCC kinase pathway and NPR-C/Gi/PLC/PKC signaling pathway mediated NCC activation. These results demonstrate that NPR-C signaling regulates NCC function contributing to sodium retention-mediated elevated blood pressure, which suggests that NPR-C is a promising candidate for the treatment of sodium retention-related hypertension.
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MESH Headings
- Angiotensin II
- Animals
- Blood Pressure/genetics
- Blood Pressure/physiology
- Cells, Cultured
- Female
- Hypertension/chemically induced
- Hypertension/genetics
- Hypertension/physiopathology
- Kidney/metabolism
- Kidney Tubules, Distal/cytology
- Kidney Tubules, Distal/metabolism
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism
- Receptors, Atrial Natriuretic Factor/deficiency
- Receptors, Atrial Natriuretic Factor/genetics
- Renin-Angiotensin System/genetics
- Renin-Angiotensin System/physiology
- Signal Transduction/genetics
- Sodium/blood
- Sodium/urine
- Solute Carrier Family 12, Member 3/genetics
- Solute Carrier Family 12, Member 3/metabolism
- Mice
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Affiliation(s)
- Shuai Shao
- From the Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
| | - Xiao-Dong Li
- From the Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
| | - Yuan-Yuan Lu
- From the Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
| | - Shi-Jin Li
- From the Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
| | - Xiao-Hui Chen
- From the Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
| | - Han-Dan Zhou
- From the Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
| | - Shun He
- From the Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
| | - Yue-Tong Guo
- From the Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
| | - Xiao Lu
- From the Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
| | - Ping-Jin Gao
- From the Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
| | - Ji-Guang Wang
- From the Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
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30
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Feng Y, Peng K, Luo R, Wang F, Yang T. Site-1 Protease-Derived Soluble (Pro)Renin Receptor Contributes to Angiotensin II-Induced Hypertension in Mice. Hypertension 2021; 77:405-416. [PMID: 33280408 PMCID: PMC7803453 DOI: 10.1161/hypertensionaha.120.15100] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated Ang II-induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histidine-tagged sPRR termed as sPRR-His. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II-induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II-induced hypertension through enhancement of intrarenal renin level and activation of ENaC.
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Affiliation(s)
- Ye Feng
- From the Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City
| | - Kexin Peng
- From the Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City
| | - Renfei Luo
- From the Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City
| | - Fei Wang
- From the Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City
| | - Tianxin Yang
- From the Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City
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31
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Preston RA, Afshartous D, Caizapanta EV, Materson BJ, Rodco R, Alonso E, Alonso AB. Thiazide-Sensitive NCC (Sodium-Chloride Cotransporter) in Human Metabolic Syndrome: Sodium Sensitivity and Potassium-Induced Natriuresis. Hypertension 2021; 77:447-460. [PMID: 33390050 DOI: 10.1161/hypertensionaha.120.15933] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The thiazide-sensitive sodium-chloride cotransporter (NCC;SLC12A3) is central to sodium and blood pressure regulation. Metabolic syndrome induces NCC upregulation generating sodium-sensitive hypertension in experimental animal models. We tested the role of NCC in sodium sensitivity in hypertensive humans with metabolic syndrome. Conversely, oral potassium induces NCC downregulation producing potassium-induced natriuresis. We determined the time course and magnitude of potassium-induced natriuresis compared with the natriuresis following hydrochlorothiazide (HCTZ) as a reference standard. We studied 19 obese hypertensive humans with metabolic syndrome during 13-day inpatient confinement. We determined sodium sensitivity by change in 24-hour mean systolic pressure by automated monitor from days 5 (low sodium) to 10 (high sodium). We determined NCC activity by standard 50 mg HCTZ sensitivity test (day 11). We determined potassium-induced natriuresis following 35 mmol KCl (day 13). We determined (1) whether NCC activity was greater in sodium-sensitive versus sodium-resistant participants and correlated with sodium sensitivity and (2) time course and magnitude of potassium-induced natriuresis following 35 mmol KCl directly compared with 50 mg HCTZ. NCC activity was not greater in sodium-sensitive versus sodium-resistant humans and did not correlate with sodium sensitivity. Thirty-five-millimoles KCl produced a rapid natriuresis approximately half that of 50 mg HCTZ with a greater kaliuresis. Our investigation tested a key hypothesis regarding NCC activity in human hypertension and characterized potassium-induced natriuresis following 35 mmol KCl compared with 50 mg HCTZ. In obese hypertensive adults with metabolic syndrome ingesting a high-sodium diet, 35 mmol KCl had a net natriuretic effect approximately half that of 50 mg HCTZ.
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Affiliation(s)
- Richard A Preston
- From the Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, Miller School of Medicine, University of Miami, FL (R.A.P., D.A., E.V.C., B.J.M., R.R., E.A., A.B.A.).,University of Miami Clinical and Translational Science Institutes, FL (R.A.P.).,Peggy and Harold Katz Family Drug Discovery Center, Miami, FL (R.A.P.)
| | - David Afshartous
- From the Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, Miller School of Medicine, University of Miami, FL (R.A.P., D.A., E.V.C., B.J.M., R.R., E.A., A.B.A.)
| | - Evelyn V Caizapanta
- From the Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, Miller School of Medicine, University of Miami, FL (R.A.P., D.A., E.V.C., B.J.M., R.R., E.A., A.B.A.)
| | - Barry J Materson
- From the Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, Miller School of Medicine, University of Miami, FL (R.A.P., D.A., E.V.C., B.J.M., R.R., E.A., A.B.A.)
| | - Rolando Rodco
- From the Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, Miller School of Medicine, University of Miami, FL (R.A.P., D.A., E.V.C., B.J.M., R.R., E.A., A.B.A.)
| | - Eileen Alonso
- From the Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, Miller School of Medicine, University of Miami, FL (R.A.P., D.A., E.V.C., B.J.M., R.R., E.A., A.B.A.)
| | - Alberto B Alonso
- From the Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, Miller School of Medicine, University of Miami, FL (R.A.P., D.A., E.V.C., B.J.M., R.R., E.A., A.B.A.)
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32
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Ochiai-Homma F, Kuribayashi-Okuma E, Tsurutani Y, Ishizawa K, Fujii W, Odajima K, Kawagoe M, Tomomitsu Y, Murakawa M, Asakawa S, Hirohama D, Nagura M, Arai S, Yamazaki O, Tamura Y, Fujigaki Y, Nishikawa T, Shibata S. Characterization of pendrin in urinary extracellular vesicles in a rat model of aldosterone excess and in human primary aldosteronism. Hypertens Res 2021; 44:1557-1567. [PMID: 34326480 PMCID: PMC8645477 DOI: 10.1038/s41440-021-00710-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 06/17/2021] [Accepted: 06/29/2021] [Indexed: 02/07/2023]
Abstract
Pendrin is a Cl-/HCO3- exchanger selectively present in the intercalated cells of the kidney. Although experimental studies have demonstrated that pendrin regulates blood pressure downstream of the renin-angiotensin-aldosterone system, its role in human hypertension remains unclear. Here, we analyzed the quantitative changes in pendrin in urinary extracellular vesicles (uEVs) isolated from a total of 30 patients with primary aldosteronism (PA) and from a rat model of aldosterone excess. Western blot analysis revealed that pendrin is present in dimeric and monomeric forms in uEVs in humans and rats. In a rodent model that received continuous infusion of aldosterone with or without concomitant administration of the selective mineralocorticoid receptor (MR) antagonist esaxerenone, pendrin levels in uEVs, as well as those of epithelial Na+ channel (ENaC) and Na-Cl-cotransporter (NCC), were highly correlated with renal abundance. In patients with PA, pendrin levels in uEVs were reduced by 49% from baseline by adrenalectomy or pharmacological MR blockade. Correlation analysis revealed that the magnitude of pendrin reduction after treatment significantly correlated with the baseline aldosterone-renin ratio (ARR). Finally, a cross-sectional analysis of patients with PA confirmed a significant correlation between the ARR and pendrin levels in uEVs. These data are consistent with experimental studies showing the role of pendrin in aldosterone excess and suggest that pendrin abundance is attenuated by therapeutic interventions in human PA. Our study also indicates that pendrin analysis in uEVs, along with other proteins, can be useful to understand the pathophysiology of hypertensive disorders.
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Affiliation(s)
- Fumika Ochiai-Homma
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Emiko Kuribayashi-Okuma
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Yuya Tsurutani
- grid.410819.50000 0004 0621 5838Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Yokohama, Japan
| | - Kenichi Ishizawa
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Wataru Fujii
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Kohei Odajima
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Mika Kawagoe
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Yoshihiro Tomomitsu
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Masataka Murakawa
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Shinichiro Asakawa
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Daigoro Hirohama
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Michito Nagura
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Shigeyuki Arai
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Osamu Yamazaki
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Yoshifuru Tamura
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Yoshihide Fujigaki
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Tetsuo Nishikawa
- grid.410819.50000 0004 0621 5838Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Yokohama, Japan
| | - Shigeru Shibata
- grid.264706.10000 0000 9239 9995Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
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33
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Zhang RM, McNerney KP, Riek AE, Bernal‐Mizrachi C. Immunity and Hypertension. Acta Physiol (Oxf) 2021; 231:e13487. [PMID: 32359222 DOI: 10.1111/apha.13487] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/24/2020] [Accepted: 04/25/2020] [Indexed: 12/15/2022]
Abstract
Hypertension is the primary cause of cardiovascular mortality. Despite multiple existing treatments, only half of those with the disease achieve adequate control. Therefore, understanding the mechanisms causing hypertension is essential for the development of novel therapies. Many studies demonstrate that immune cell infiltration of the vessel wall, kidney and central nervous system, as well as their counterparts of oxidative stress, the renal renin-angiotensin system (RAS) and sympathetic tone play a critical role in the development of hypertension. Genetically modified mice lacking components of innate and/or adaptive immunity confirm the importance of chronic inflammation in hypertension and its complications. Depletion of immune cells improves endothelial function, decreases oxidative stress, reduces vascular tone and prevents renal interstitial infiltrates, sodium retention and kidney damage. Moreover, the ablation of microglia or central nervous system perivascular macrophages reduces RAS-induced inflammation and prevents sympathetic nervous system activation and hypertension. Therefore, understanding immune cell functioning and their interactions with tissues that regulate hypertensive responses may be the future of novel antihypertensive therapies.
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Affiliation(s)
- Rong M. Zhang
- Department of Medicine Division of Endocrinology, Metabolism, and Lipid Research Washington University School of Medicine St. Louis MO USA
| | - Kyle P. McNerney
- Department of Pediatrics Washington University School of Medicine St. Louis MO USA
| | - Amy E. Riek
- Department of Medicine Division of Endocrinology, Metabolism, and Lipid Research Washington University School of Medicine St. Louis MO USA
| | - Carlos Bernal‐Mizrachi
- Department of Medicine Division of Endocrinology, Metabolism, and Lipid Research Washington University School of Medicine St. Louis MO USA
- Department of Cell Biology and Physiology Washington University School of Medicine St. Louis MO USA
- Department of Medicine VA Medical Center St. Louis MO USA
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Effect of sodium bicarbonate supplementation on the renin-angiotensin system in patients with chronic kidney disease and acidosis: a randomized clinical trial. J Nephrol 2020; 34:1737-1745. [PMID: 33382448 PMCID: PMC8494695 DOI: 10.1007/s40620-020-00944-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 11/30/2020] [Indexed: 12/21/2022]
Abstract
Background Acidosis-induced kidney injury is mediated by the intrarenal renin-angiotensin system, for which urinary renin is a potential marker. Therefore, we hypothesized that sodium bicarbonate supplementation reduces urinary renin excretion in patients with chronic kidney disease (CKD) and metabolic acidosis. Methods Patients with CKD stage G4 and plasma bicarbonate 15–24 mmol/l were randomized to receive sodium bicarbonate (3 × 1000 mg/day, ~ 0.5 mEq/kg), sodium chloride (2 × 1,00 mg/day), or no treatment for 4 weeks (n = 15/arm). The effects on urinary renin excretion (primary outcome), other plasma and urine parameters of the renin-angiotensin system, endothelin-1, and proteinuria were analyzed. Results Forty-five patients were included (62 ± 15 years, eGFR 21 ± 5 ml/min/1.73m2, plasma bicarbonate 21.7 ± 3.3 mmol/l). Sodium bicarbonate supplementation increased plasma bicarbonate (20.8 to 23.8 mmol/l) and reduced urinary ammonium excretion (15 to 8 mmol/day, both P < 0.05). Furthermore, a trend towards lower plasma aldosterone (291 to 204 ng/L, P = 0.07) and potassium (5.1 to 4.8 mmol/l, P = 0.06) was observed in patients receiving sodium bicarbonate. Sodium bicarbonate did not significantly change the urinary excretion of renin, angiotensinogen, aldosterone, endothelin-1, albumin, or α1-microglobulin. Sodium chloride supplementation reduced plasma renin (166 to 122 ng/L), and increased the urinary excretions of angiotensinogen, albumin, and α1-microglobulin (all P < 0.05). Conclusions Despite correction of acidosis and reduction in urinary ammonium excretion, sodium bicarbonate supplementation did not improve urinary markers of the renin-angiotensin system, endothelin-1, or proteinuria. Possible explanations include bicarbonate dose, short treatment time, or the inability of urinary renin to reflect intrarenal renin-angiotensin system activity. Graphic abstract ![]()
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Marahrens B, Schulze A, Wysocki J, Lin MH, Ye M, Kanwar YS, Bader M, Velez JCQ, Miner JH, Batlle D. Knockout of aminopeptidase A in mice causes functional alterations and morphological glomerular basement membrane changes in the kidneys. Kidney Int 2020; 99:900-913. [PMID: 33316280 DOI: 10.1016/j.kint.2020.11.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 10/28/2020] [Accepted: 11/19/2020] [Indexed: 11/29/2022]
Abstract
Aminopeptidase A is one of the most potent enzymes within the renin-angiotensin system in terms of angiotensin II degradation. Here, we examined whether there is a kidney phenotype and any compensatory changes in other renin angiotensin system enzymes involved in the metabolism of angiotensin II associated with aminopeptidase A deficiency. Kidneys harvested from aminopeptidase A knockout mice were examined by light and electron microscopy, immunohistochemistry and immunofluorescence. Kidney angiotensin II levels and the ability of renin angiotensin system enzymes in the glomerulus to degrade angiotensin II ex vivo, their activities, protein and mRNA levels in kidney lysates were evaluated. Knockout mice had increased blood pressure and mild glomerular mesangial expansion without significant albuminuria. By electron microscopy, knockout mice exhibited a mild increase of the mesangial matrix, moderate thickening of the glomerular basement membrane but a striking appearance of knob-like structures. These knobs were seen in both male and female mice and persisted after the treatment of hypertension. In isolated glomeruli from knockout mice, the level of angiotensin II was more than three-fold higher as compared to wild type control mice. In kidney lysates from knockout mice angiotensin converting enzyme activity, protein and mRNA levels were markedly decreased possibly as a compensatory mechanism to reduce angiotensin II formation. Thus, our findings support a role for aminopeptidase A in the maintenance of glomerular structure and intra-kidney homeostasis of angiotensin peptides.
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Affiliation(s)
- Benedikt Marahrens
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University/Feinberg School of Medicine, Chicago, Illinois, USA; Charité University Medicine Berlin, Berlin, Germany
| | - Arndt Schulze
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University/Feinberg School of Medicine, Chicago, Illinois, USA; Charité University Medicine Berlin, Berlin, Germany
| | - Jan Wysocki
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University/Feinberg School of Medicine, Chicago, Illinois, USA
| | - Meei-Hua Lin
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Minghao Ye
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University/Feinberg School of Medicine, Chicago, Illinois, USA
| | - Yashpal S Kanwar
- Department of Pathology, Northwestern University/Feinberg School of Medicine, Chicago, Illinois, USA
| | - Michael Bader
- Charité University Medicine Berlin, Berlin, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Institute for Biology, University of Lübeck, Lübeck, Germany
| | - Juan Carlos Q Velez
- Department of Nephrology, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
| | - Jeffrey H Miner
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Daniel Batlle
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University/Feinberg School of Medicine, Chicago, Illinois, USA.
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Curnow AC, Gonsalez SR, Gogulamudi VR, Visniauskas B, Simon EE, Gonzalez AA, Majid DSA, Lara LS, Prieto MC. Low Nitric Oxide Bioavailability Increases Renin Production in the Collecting Duct. Front Physiol 2020; 11:559341. [PMID: 33281610 PMCID: PMC7705222 DOI: 10.3389/fphys.2020.559341] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 10/21/2020] [Indexed: 12/14/2022] Open
Abstract
In the kidney, the stimulation of renin production by the collecting duct (CD-renin) contributes to the development of hypertension. The CD is a major nephron segment for the synthesis of nitric oxide (NO), and low NO bioavailability in the renal medulla is associated with hypertension. However, it is unknown whether NO regulates renin production in the CD. To test the hypothesis that low intrarenal NO levels stimulate the production of CD-renin, we first examined renin expression in the distal nephron segments of CD-eNOS deficient mice. In these mice, specific CD-renin immunoreactivity was increased compared to wild-type littermates; however, juxtaglomerular (JG) renin was not altered. To further assess the intracellular mechanisms involved, we then treated M-1 cells with either 1 mM L-NAME (L-arginine analog), an inhibitor of NO synthase activity, or 1 mM NONOate, a NO donor. Both treatments increased intracellular renin protein levels in M-1 cells. However, only the inhibition of NOS with L-NAME stimulated renin synthesis and secretion as reflected by the increase in Ren1C transcript and renin protein levels in the extracellular media, respectively. In addition, NONOate induced a fast mobilization of cGMP and intracellular renin accumulation. These response was partially prevented by guanylyl cyclase inhibition with ODQ (1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1]. Accumulation of intracellular renin was blocked by protein kinase G (PKG) and protein kinase C (PKC) inhibitors. Our data indicate that low NO bioavailability increases CD-renin synthesis and secretion, which may contribute to the activation of intrarenal renin angiotensin system.
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Affiliation(s)
- Andrew C. Curnow
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Sabrina R. Gonsalez
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Bruna Visniauskas
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Eric E. Simon
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States
| | - Alexis A. Gonzalez
- Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Dewan S. A. Majid
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
- Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States
| | - Lucienne S. Lara
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Minolfa C. Prieto
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
- Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States
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Gao L, Yuan P, Zhang Q, Fu Y, Hou Y, Wei Y, Zheng X, Feng W. Taxifolin improves disorders of glucose metabolism and water-salt metabolism in kidney via PI3K/AKT signaling pathway in metabolic syndrome rats. Life Sci 2020; 263:118713. [PMID: 33157091 DOI: 10.1016/j.lfs.2020.118713] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/23/2020] [Accepted: 11/02/2020] [Indexed: 12/16/2022]
Abstract
AIMS Our study was designed to explore the function and mechanism of taxifolin on glucose metabolism and water-salt metabolism in kidney with metabolic syndrome (MS) rats. MAIN METHODS Spontaneous hypertensive rats were induced by fructose to establish MS model. Systolic blood pressure (SBP) and homeostasis model assessment of insulin resistance (HOMA-IR) were measured after 7 weeks of continuous administration with taxifolin. Kidney injury indices and histopathological evaluation were done. The apoptosis rate of primary kidney cells was detected by flow cytometry. Insulin signaling pathway related proteins and renal glucose transport-related proteins were detected by western blotting. We assessed the effects of taxifolin on sodium water retention and renin-angiotensin-aldosterone system (RAAS) in MS rats. We examined not only changes in urine volume, osmotic pressure, urinary sodium and urinary chloride excretion, but also the effects on NA+/K+-ATPase and RAAS indicators. We also detected changes in inflammatory factors by immunohistochemical staining and immunofluorescence. In vitro experiment, high glucose and salt stimulated NRK-52E cells. By adding the PI3K inhibitor (wortmannin) to inhibit the PI3K, the effects of inhibiting the PI3K/AKT signaling pathway on glucose metabolism, water-sodium retention and inflammatory response were discussed. KEY FINDINGS Taxifolin effectively reversed SBP, HOMA-IR, the kidney indices and abnormal histopathological changes induced by MS. Besides, taxifolin called back the protein associated with the downstream glucose metabolism pathway of PI3K/AKT. It also inhibited overactivation of RAAS and inflammatory response. In vitro experiments have demonstrated that the PI3K/AKT signaling pathway plays an important role in this process. SIGNIFICANCE Taxifolin can improve homeostasis of glucose, inhibit overactivation of RAAS and reduce inflammatory response by PI3K/AKT signaling pathway.
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Affiliation(s)
- Liyuan Gao
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Peipei Yuan
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Qi Zhang
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yang Fu
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Ying Hou
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yaxin Wei
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Xiaoke Zheng
- Henan University of Chinese Medicine, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China.
| | - Weisheng Feng
- Henan University of Chinese Medicine, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China.
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Bovée DM, Cuevas CA, Zietse R, Danser AHJ, Mirabito Colafella KM, Hoorn EJ. Salt-sensitive hypertension in chronic kidney disease: distal tubular mechanisms. Am J Physiol Renal Physiol 2020; 319:F729-F745. [DOI: 10.1152/ajprenal.00407.2020] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Chronic kidney disease (CKD) causes salt-sensitive hypertension that is often resistant to treatment and contributes to the progression of kidney injury and cardiovascular disease. A better understanding of the mechanisms contributing to salt-sensitive hypertension in CKD is essential to improve these outcomes. This review critically explores these mechanisms by focusing on how CKD affects distal nephron Na+ reabsorption. CKD causes glomerulotubular imbalance with reduced proximal Na+ reabsorption and increased distal Na+ delivery and reabsorption. Aldosterone secretion further contributes to distal Na+ reabsorption in CKD and is not only mediated by renin and K+ but also by metabolic acidosis, endothelin-1, and vasopressin. CKD also activates the intrarenal renin-angiotensin system, generating intratubular angiotensin II to promote distal Na+ reabsorption. High dietary Na+ intake in CKD contributes to Na+ retention by aldosterone-independent activation of the mineralocorticoid receptor mediated through Rac1. High dietary Na+ also produces an inflammatory response mediated by T helper 17 cells and cytokines increasing distal Na+ transport. CKD is often accompanied by proteinuria, which contains plasmin capable of activating the epithelial Na+ channel. Thus, CKD causes both local and systemic changes that together promote distal nephron Na+ reabsorption and salt-sensitive hypertension. Future studies should address remaining knowledge gaps, including the relative contribution of each mechanism, the influence of sex, differences between stages and etiologies of CKD, and the clinical relevance of experimentally identified mechanisms. Several pathways offer opportunities for intervention, including with dietary Na+ reduction, distal diuretics, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and K+ or H+ binders.
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Affiliation(s)
- Dominique M. Bovée
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
- Division of Vascular Medicine, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Catharina A. Cuevas
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Robert Zietse
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - A. H. Jan Danser
- Division of Vascular Medicine, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Katrina M. Mirabito Colafella
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
- Department of Physiology, Monash University, Melbourne, Victoria, Australia
| | - Ewout J. Hoorn
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
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Markó L, Park JK, Henke N, Rong S, Balogh A, Klamer S, Bartolomaeus H, Wilck N, Ruland J, Forslund SK, Luft FC, Dechend R, Müller DN. B-cell lymphoma/leukaemia 10 and angiotensin II-induced kidney injury. Cardiovasc Res 2020; 116:1059-1070. [PMID: 31241148 DOI: 10.1093/cvr/cvz169] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 01/09/2019] [Accepted: 06/21/2019] [Indexed: 12/30/2022] Open
Abstract
AIMS B-cell lymphoma/leukaemia 10 (Bcl10) is a member of the CARMA-Bcl10-MALT1 signalosome, linking angiotensin (Ang) II, and antigen-dependent immune-cell activation to nuclear factor kappa-B signalling. We showed earlier that Bcl10 plays a role in Ang II-induced cardiac fibrosis and remodelling, independent of blood pressure. We now investigated the role of Bcl10 in Ang II-induced renal damage. METHODS AND RESULTS Bcl10 knockout mice (Bcl10 KO) and wild-type (WT) controls were given 1% NaCl in the drinking water and Ang II (1.44 mg/kg/day) for 14 days. Additionally, Bcl10 KO or WT kidneys were transplanted onto WT mice that were challenged by the same protocol for 7 days. Kidneys of Ang II-treated Bcl10 KO mice developed less fibrosis and showed fewer infiltrating cells. Nevertheless, neutrophil gelatinase-associated lipocalin (Ngal) and kidney injury molecule (Kim)1 expression was higher in the kidneys of Ang II-treated Bcl10 KO mice, indicating exacerbated tubular damage. Furthermore, albuminuria was significantly higher in Ang II-treated Bcl10 KO mice accompanied by reduced glomerular nephrin expression and podocyte number. Ang II-treated WT mice transplanted with Bcl10 KO kidney showed more albuminuria and renal Ngal, compared to WT- > WT kidney-transplanted mice, as well as lower podocyte number but similar fibrosis and cell infiltration. Interestingly, mice lacking Bcl10 in the kidney exhibited less Ang II-induced cardiac hypertrophy than controls. CONCLUSION Bcl10 has multi-faceted actions in Ang II-induced renal damage. On the one hand, global Bcl10 deficiency ameliorates renal fibrosis and cell infiltration; on the other hand, lack of renal Bcl10 aggravates albuminuria and podocyte damage. These data suggest that Bcl10 maintains podocyte integrity and renal function.
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Affiliation(s)
- Lajos Markó
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin, Berlin, Germany and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,Charité-Universitätsmedizin Berlin, Berlin, Germany
| | | | | | - Song Rong
- Hannover Medical School, Hannover, Germany.,Transplantation Center, Zunyi Medical College, Zunyi, China
| | - András Balogh
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin, Berlin, Germany and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Samuel Klamer
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin, Berlin, Germany and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany
| | - Hendrik Bartolomaeus
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin, Berlin, Germany and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,Charité-Universitätsmedizin Berlin, Berlin, Germany.,Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Nicola Wilck
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin, Berlin, Germany and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Jürgen Ruland
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), Munich, Germany.,German Cancer Consortium (DKTK), partner Site, Munich, Germany
| | - Sofia K Forslund
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin, Berlin, Germany and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,Charité-Universitätsmedizin Berlin, Berlin, Germany.,Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Friedrich C Luft
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin, Berlin, Germany and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.,Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Ralf Dechend
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin, Berlin, Germany and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,Charité-Universitätsmedizin Berlin, Berlin, Germany.,Helios Clinic Berlin-Buch, Berlin, Germany
| | - Dominik N Müller
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin, Berlin, Germany and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,Charité-Universitätsmedizin Berlin, Berlin, Germany.,Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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McFarlin BE, Chen Y, Priver TS, Ralph DL, Mercado A, Gamba G, Madhur MS, McDonough AA. Coordinate adaptations of skeletal muscle and kidney to maintain extracellular [K +] during K +-deficient diet. Am J Physiol Cell Physiol 2020; 319:C757-C770. [PMID: 32845718 PMCID: PMC7654654 DOI: 10.1152/ajpcell.00362.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/17/2020] [Accepted: 08/19/2020] [Indexed: 12/16/2022]
Abstract
Extracellular fluid (ECF) potassium concentration ([K+]) is maintained by adaptations of kidney and skeletal muscle, responses heretofore studied separately. We aimed to determine how these organ systems work in concert to preserve ECF [K+] in male C57BL/6J mice fed a K+-deficient diet (0K) versus 1% K+ diet (1K) for 10 days (n = 5-6/group). During 0K feeding, plasma [K+] fell from 4.5 to 2 mM; hindlimb muscle (gastrocnemius and soleus) lost 28 mM K+ (from 115 ± 2 to 87 ± 2 mM) and gained 27 mM Na+ (from 27 ± 0.4 to 54 ± 2 mM). Doubling of muscle tissue [Na+] was not associated with inflammation, cytokine production or hypertension as reported by others. Muscle transporter adaptations in 0K- versus 1K-fed mice, assessed by immunoblot, included decreased sodium pump α2-β2 subunits, decreased K+-Cl- cotransporter isoform 3, and increased phosphorylated (p) Na+,K+,2Cl- cotransporter isoform 1 (NKCC1p), Ste20/SPS-1-related proline-alanine rich kinase (SPAKp), and oxidative stress-responsive kinase 1 (OSR1p) consistent with intracellular fluid (ICF) K+ loss and Na+ gain. Renal transporters' adaptations, effecting a 98% reduction in K+ excretion, included two- to threefold increased phosphorylated Na+-Cl- cotransporter (NCCp), SPAKp, and OSR1p abundance, limiting Na+ delivery to epithelial Na+ channels where Na+ reabsorption drives K+ secretion; and renal K sensor Kir 4.1 abundance fell 25%. Mass balance estimations indicate that over 10 days of 0K feeding, mice lose ~48 μmol K+ into the urine and muscle shifts ~47 μmol K+ from ICF to ECF, illustrating the importance of the concerted responses during K+ deficiency.
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Affiliation(s)
- Brandon E McFarlin
- Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Yuhan Chen
- Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cardiology, Nanjing University Medical School, Nanjing, China
| | - Taylor S Priver
- Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Donna L Ralph
- Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Adriana Mercado
- Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Gerardo Gamba
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Meena S Madhur
- Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Alicia A McDonough
- Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, California
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FNDC5 Attenuates Oxidative Stress and NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells via Activating the AMPK-SIRT1 Signal Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6384803. [PMID: 32509148 PMCID: PMC7254086 DOI: 10.1155/2020/6384803] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 03/18/2020] [Accepted: 04/16/2020] [Indexed: 01/09/2023]
Abstract
Vascular oxidative stress and inflammation play a major role in vascular diseases. This study was aimed at determining the protective roles of fibronectin type III domain-containing 5 (FNDC5) in angiotensin II- (Ang II-) induced vascular oxidative stress and inflammation and underlying mechanisms. Wild-type (WT) and FNDC5−/− mice, primary mouse vascular smooth muscle cells (VSMCs), and the rat aortic smooth muscle cell line (A7R5) were used in the present study. Subcutaneous infusion of Ang II caused more serious hypertension, vascular remodeling, oxidative stress, NLRP3 inflammasome activation, AMPK phosphorylation inhibition, and SIRT1 downregulation in the aorta of FNDC5−/− mice than those of WT mice. Exogenous FNDC5 attenuated Ang II-induced superoxide generation, NADPH oxidase 2 (NOX2) and NLRP3 upregulation, mature caspase-1, and interleukin-1β (IL-1β) production in A7R5 cells. The protective roles of FNDC5 were prevented by SIRT-1 inhibitor EX527, AMPK inhibitor compound C, or integrin receptor inhibitor GLPG0187. FNDC5 attenuated the Ang II-induced inhibition in SIRT1 activity, SIRT1 protein expression, and AMPKα phosphorylation in A7R5 cells, which were prevented by compound C, EX527, and GLPG0187. FNDC5 deficiency deteriorated Ang II-induced oxidative stress, NLRP3 inflammasome activation, AMPK phosphorylation inhibition, and SIRT1 downregulation in primary aortic VSMCs of mice, which were prevented by exogenous FNDC5. These results indicate that FNDC5 deficiency aggravates while exogenous FNDC5 alleviates the Ang II-induced vascular oxidative stress and NLRP3 inflammasome activation via the AMPK-SIRT1 signal pathway in VSMCs.
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Veiras LC, McFarlin BE, Ralph DL, Buncha V, Prescott J, Shirvani BS, McDonough JC, Ha D, Giani J, Gurley SB, Mamenko M, McDonough AA. Electrolyte and transporter responses to angiotensin II induced hypertension in female and male rats and mice. Acta Physiol (Oxf) 2020; 229:e13448. [PMID: 31994810 DOI: 10.1111/apha.13448] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 01/21/2020] [Accepted: 01/23/2020] [Indexed: 12/15/2022]
Abstract
AIM Sexual dimorphisms are evident along the nephron: Females (F) exhibit higher ratios of renal distal to proximal Na+ transporters' abundance, greater lithium clearance (CLi ) more rapid natriuresis in response to saline infusion and lower plasma [K+ ] vs. males (M). During angiotensin II infusion hypertension (AngII-HTN) M exhibit distal Na+ transporter activation, lower proximal and medullary loop transporters, blunted natriuresis in response to saline load, and reduced plasma [K+ ]. This study aimed to determine whether responses of F to AngII-HTN mimicked those in M or were impacted by sexual dimorphisms evident at baseline. METHODS Sprague Dawley rats and C57BL/6 mice were AngII infused via osmotic minipumps 2 and 3 weeks, respectively, and assessed by metabolic cage collections, tail-cuff sphygmomanometer, semi-quantitative immunoblotting of kidney and patch-clamp electrophysiology. RESULTS In F rats, AngII-infusion increased BP to 190 mm Hg, increased phosphorylation of cortical NKCC2, NCC and cleavage of ENaC two to threefold, increased ENaC channel activity threefold and aldosterone 10-fold. K+ excretion increased and plasma [K+ ] decreased. Evidence of natriuresis in F included increased urine Na+ excretion and CLi , and decreased medullary NHE3, NKCC2 and Na,K-ATPase abundance. In C57BL/6 mice, AngII-HTN increased abundance of distal Na+ transporters, suppressed proximal-medullary transporters and reduced plasma [K+ ] in both F and M. CONCLUSION Despite baseline sexual dimorphisms, AngII-HTN provokes similar increases in BP, aldosterone, distal transporters, ENaC channel activation and K+ loss accompanied by similar suppression of proximal and loop Na+ transporters, natriuresis and diuresis in females and males.
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Affiliation(s)
- Luciana C. Veiras
- Department of Physiology and Neuroscience Keck School of Medicine of USC Los Angeles CA USA
- Department of Biomedical Sciences Cedars‐Sinai Medical Center Los Angeles CA USA
| | - Brandon E. McFarlin
- Department of Physiology and Neuroscience Keck School of Medicine of USC Los Angeles CA USA
| | - Donna L. Ralph
- Department of Physiology and Neuroscience Keck School of Medicine of USC Los Angeles CA USA
| | - Vadym Buncha
- Department of Physiology Medical College of Georgia at Augusta University Augusta GA USA
| | - Jessica Prescott
- Department of Physiology and Neuroscience Keck School of Medicine of USC Los Angeles CA USA
| | - Borna S. Shirvani
- Department of Physiology and Neuroscience Keck School of Medicine of USC Los Angeles CA USA
| | - Jillian C. McDonough
- Department of Physiology and Neuroscience Keck School of Medicine of USC Los Angeles CA USA
| | - Darren Ha
- Department of Physiology and Neuroscience Keck School of Medicine of USC Los Angeles CA USA
| | - Jorge Giani
- Department of Biomedical Sciences Cedars‐Sinai Medical Center Los Angeles CA USA
| | - Susan B. Gurley
- Division of Nephrology and Hypertension Oregon Health and Science University Portland OR USA
| | - Mykola Mamenko
- Department of Physiology Medical College of Georgia at Augusta University Augusta GA USA
| | - Alicia A. McDonough
- Department of Physiology and Neuroscience Keck School of Medicine of USC Los Angeles CA USA
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43
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Furusho T, Uchida S, Sohara E. The WNK signaling pathway and salt-sensitive hypertension. Hypertens Res 2020; 43:733-743. [PMID: 32286498 DOI: 10.1038/s41440-020-0437-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 03/11/2020] [Accepted: 03/11/2020] [Indexed: 12/19/2022]
Abstract
The distal nephron of the kidney has a central role in sodium and fluid homeostasis, and disruption of this homeostasis due to mutations of with-no-lysine kinase 1 (WNK1), WNK4, Kelch-like 3 (KLHL3), or Cullin 3 (CUL3) causes pseudohypoaldosteronism type II (PHAII), an inherited hypertensive disease. WNK1 and WNK4 activate the NaCl cotransporter (NCC) at the distal convoluted tubule through oxidative stress-responsive gene 1 (OSR1)/Ste20-related proline-alanine-rich kinase (SPAK), constituting the WNK-OSR1/SPAK-NCC phosphorylation cascade. The level of WNK protein is regulated through degradation by the CUL3-KLHL3 E3 ligase complex. In the normal state, the activity of WNK signaling in the kidney is physiologically regulated by sodium intake to maintain sodium homeostasis in the body. In patients with PHAII, however, because of the defective degradation of WNK kinases, NCC is constitutively active and not properly suppressed by a high salt diet, leading to abnormally increased salt reabsorption and salt-sensitive hypertension. Importantly, recent studies have demonstrated that potassium intake, insulin, and TNFα are also physiological regulators of WNK signaling, suggesting that they contribute to the salt-sensitive hypertension associated with a low potassium diet, metabolic syndrome, and chronic kidney disease, respectively. Moreover, emerging evidence suggests that WNK signaling also has some unique roles in metabolic, cardiovascular, and immunological organs. Here, we review the recent literature and discuss the molecular mechanisms of the WNK signaling pathway and its potential as a therapeutic target.
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Affiliation(s)
- Taisuke Furusho
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinichi Uchida
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Eisei Sohara
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
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44
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Hering L, Rahman M, Hoch H, Markó L, Yang G, Reil A, Yakoub M, Gupta V, Potthoff SA, Vonend O, Ralph DL, Gurley SB, McDonough AA, Rump LC, Stegbauer J. α2A-Adrenoceptors Modulate Renal Sympathetic Neurotransmission and Protect against Hypertensive Kidney Disease. J Am Soc Nephrol 2020; 31:783-798. [PMID: 32086277 DOI: 10.1681/asn.2019060599] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 12/30/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown. METHODS We investigated effects of α2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days. RESULTS Urinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor-knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor-knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor-deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor-knockout mice after renal denervation. CONCLUSIONS Our findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.
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Affiliation(s)
- Lydia Hering
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Masudur Rahman
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Henning Hoch
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Lajos Markó
- Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbruck Center for Molecular Medicine, Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Berlin, Germany.,Berlin Institute of Health, Berlin, Germany.,Charité Medical Faculty Berlin, Berlin, Germany
| | - Guang Yang
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
| | - Annika Reil
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Mina Yakoub
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Vikram Gupta
- Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Sebastian A Potthoff
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Oliver Vonend
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Nierenzentrum, DKD Helios Medical Center, Wiesbaden, Germany
| | - Donna L Ralph
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California; and
| | - Susan B Gurley
- Division of Nephrology and Hypertension, School of Medicine, Oregon Health and Science University, Portland, Oregon
| | - Alicia A McDonough
- Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California; and
| | - Lars C Rump
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Johannes Stegbauer
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany;
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45
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Furusho T, Sohara E, Mandai S, Kikuchi H, Takahashi N, Fujimaru T, Hashimoto H, Arai Y, Ando F, Zeniya M, Mori T, Susa K, Isobe K, Nomura N, Yamamoto K, Okado T, Rai T, Uchida S. Renal TNFα activates the WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease. Kidney Int 2020; 97:713-727. [PMID: 32059997 DOI: 10.1016/j.kint.2019.11.021] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 11/19/2019] [Accepted: 11/22/2019] [Indexed: 12/13/2022]
Abstract
The inappropriate over-activation of the with-no-lysine kinase (WNK)-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-sodium chloride cotransporter (NCC) phosphorylation cascade increases sodium reabsorption in distal kidney nephrons, resulting in salt-sensitive hypertension. Although chronic kidney disease (CKD) is a common cause of salt-sensitive hypertension, the involvement of the WNK phosphorylation cascade is unknown. Moreover, the effect of immune systems on WNK kinases has not been investigated despite the fact that immune systems are important for salt sensitivity. Here we demonstrate that the protein abundance of WNK1, but not of WNK4, was increased at the distal convoluted tubules in the aristolochic acid nephropathy mouse model of CKD. Accordingly, the phosphorylation of both SPAK and NCC was also increased. Moreover, a high-salt diet did not adequately suppress activation of the WNK1-SPAK-NCC phosphorylation cascade in this model, leading to salt-sensitive hypertension. WNK1 also was increased in adenine nephropathy, but not in subtotal nephrectomy, models of CKD. By comparing the transcripts of these three models focusing on immune systems, we hypothesized that tumor necrosis factor (TNF)-α regulates WNK1 protein expression. In fact, TNF-α increased WNK1 protein expression in cultured renal tubular cells by reducing the transcription and protein levels of NEDD4-2 E3-ligase, which degrades WNK1 protein. Furthermore, the TNF-α inhibitor etanercept reversed the reduction of NEDD4-2 expression and upregulation of the WNK1-SPAK-NCC phosphorylation cascade in distal convoluted tubules in vivo in the aristolochic acid nephropathy model. Thus, salt-sensitive hypertension is induced in CKD via activation of the renal WNK1- SPAK-NCC phosphorylation cascade by TNF-α, reflecting a link with the immune system.
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Affiliation(s)
- Taisuke Furusho
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Eisei Sohara
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
| | - Shintaro Mandai
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroaki Kikuchi
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Naohiro Takahashi
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takuya Fujimaru
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroko Hashimoto
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yohei Arai
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Fumiaki Ando
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Moko Zeniya
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takayasu Mori
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Koichiro Susa
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kiyoshi Isobe
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Naohiro Nomura
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kohei Yamamoto
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomokazu Okado
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tatemitsu Rai
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinichi Uchida
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
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46
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Zhu Y, Cui H, Lv J, Liang H, Zheng Y, Wang S, Wang M, Wang H, Ye F. AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice. Sci Rep 2019; 9:19450. [PMID: 31857626 PMCID: PMC6923374 DOI: 10.1038/s41598-019-55550-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 10/24/2019] [Indexed: 01/13/2023] Open
Abstract
Abnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.
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Affiliation(s)
- Yongjun Zhu
- Department of Nephrology, The First Affiliated Hospital of Hainan Medical University, Hainan, China.
| | - Hongwang Cui
- Department of Orthopedics, The First Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Jie Lv
- The First Clinical College of Hainan Medical University, Hainan, China
| | - Haiqin Liang
- Department of Nephrology, The First Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Yanping Zheng
- Department of Nephrology, The First Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Shanzhi Wang
- Department of Nephrology, The First Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Min Wang
- Department of Nephrology, The First Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Huanan Wang
- Department of Nephrology, The First Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Feng Ye
- Department of Nephrology, The First Affiliated Hospital of Hainan Medical University, Hainan, China.
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47
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Zhang D, Pollock DM. Diurnal Regulation of Renal Electrolyte Excretion: The Role of Paracrine Factors. Annu Rev Physiol 2019; 82:343-363. [PMID: 31635525 DOI: 10.1146/annurev-physiol-021119-034446] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Many physiological processes, including most kidney-related functions, follow specific rhythms tied to a 24-h cycle. This is largely because circadian genes operate in virtually every cell type in the body. In addition, many noncanonical genes have intrinsic circadian rhythms, especially within the liver and kidney. This new level of complexity applies to the control of renal electrolyte excretion. Furthermore, there is growing evidence that paracrine and autocrine factors, especially the endothelin system, are regulated by clock genes. We have known for decades that excretion of electrolytes is dependent on time of day, which could play an important role in fluid volume balance and blood pressure control. Here, we review what is known about the interplay between paracrine and circadian control of electrolyte excretion. The hope is that recognition of paracrine and circadian factors can be considered more deeply in the future when integrating with well-established neuroendocrine control of excretion.
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Affiliation(s)
- Dingguo Zhang
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA; ,
| | - David M Pollock
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA; ,
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48
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Gonzalez AA, Gallardo M, Cespedes C, Vio CP. Potassium Intake Prevents the Induction of the Renin-Angiotensin System and Increases Medullary ACE2 and COX-2 in the Kidneys of Angiotensin II-Dependent Hypertensive Rats. Front Pharmacol 2019; 10:1212. [PMID: 31680980 PMCID: PMC6804396 DOI: 10.3389/fphar.2019.01212] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 09/20/2019] [Indexed: 01/13/2023] Open
Abstract
In angiotensin II (Ang II)-dependent hypertensive rats there is an increased expression of proximal tubule angiotensinogen (AGT), collecting duct renin and angiotensin converting enzyme (ACE), which contributes to intratubular Ang II formation. Ang II acts on Ang II type 1 receptors promoting sodium retention and vasoconstriction. However concurrently, the ACE2-Ang-(1–7) axis and the expression of kallikrein and medullary prostaglandins counteract the effects of Ang II, promoting natriuresis and vasodilation. Human studies demonstrate that dietary potassium (K+) intake lowers blood pressure. In this report we evaluate the expression of AGT, ACE, medullary prorenin/renin, ACE2, kallikrein and cyclooxygenase-2 (COX-2) in Ang II-infused rats fed with high K+ diet (2%) for 14 days. Dietary K+ enhances diuresis in non-infused and in Ang II-infused rats. The rise in systolic blood pressure in Ang II-infused rats was attenuated by dietary K+. Ang II-infused rats showed increased renal protein levels of AGT, ACE and medullary prorenin and renin. This effect was attenuated in the Ang II + K+ group. Ang II infusion decreased ACE2 compared to the control group; however, K+ diet prevented this effect in the renal medulla. Furthermore, medullary COX-2 was dramatically induced by K+ diet in non-infused and in Ang II infused rats. Dietary K+ greatly increased kallikrein immunostaining in normotensive rats and in Ang II-hypertensive rats. These results indicate that a high K+ diet attenuates Ang II-dependent hypertension by preventing the induction of ACE, AGT and collecting duct renin and by enhancing medullary COX-2 and ACE2 protein expression in the kidney.
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Affiliation(s)
- Alexis A Gonzalez
- Institute of Chemistry, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Matias Gallardo
- Institute of Chemistry, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Carlos Cespedes
- Department of Physiology, Center for Aging and Regeneration CARE UC, Pontificia Universidad Católica de Chile, Santiago, Chile.,Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Carlos P Vio
- Department of Physiology, Center for Aging and Regeneration CARE UC, Pontificia Universidad Católica de Chile, Santiago, Chile.,Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
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49
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Okwan-Duodu D, Weiss D, Peng Z, Veiras LC, Cao DY, Saito S, Khan Z, Bernstein EA, Giani JF, Taylor WR, Bernstein KE. Overexpression of myeloid angiotensin-converting enzyme (ACE) reduces atherosclerosis. Biochem Biophys Res Commun 2019; 520:573-579. [PMID: 31615657 DOI: 10.1016/j.bbrc.2019.10.078] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 10/09/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND Macrophages are ubiquitous in all stages of atherosclerosis, exerting tremendous impact on lesion progression and plaque stability. Because macrophages in atherosclerotic plaques express angiotensin-converting enzyme (ACE), current dogma posits that local myeloid-mediated effects worsen the disease. In contrast, we previously reported that myeloid ACE overexpression augments macrophage resistance to various immune challenges, including tumors, bacterial infection and Alzheimer's plaque deposition. Here, we sought to assess the impact of myeloid ACE on atherosclerosis. METHODS A mouse model in which ACE is overexpressed in myelomonocytic lineage cells, called ACE10, was generated and sequentially crossed with ApoE-deficient mice to create ACE10/10ApoE-/- (ACE10/ApoE). Control mice were ACEWT/WTApoE-/- (WT/ApoE). Atherosclerosis was induced using an atherogenic diet alone, or in combination with unilateral nephrectomy plus deoxycorticosterone acetate (DOCA) salt for eight weeks. RESULTS With an atherogenic diet alone or in combination with DOCA, the ACE10/ApoE mice showed significantly less atherosclerotic plaques compared to their WT/ApoE counterparts (p < 0.01). When recipient ApoE-/- mice were reconstituted with ACE10/10 bone marrow, these mice showed significantly reduced lesion areas compared to recipients reconstituted with wild type bone marrow. Furthermore, transfer of ACE-deficient bone marrow had no impact on lesion area. CONCLUSION Our data indicate that while myeloid ACE may not be required for atherosclerosis, enhanced ACE expression paradoxically reduced disease progression.
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Affiliation(s)
- Derick Okwan-Duodu
- Department of Biomedical Sciences Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Daiana Weiss
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Zhenzi Peng
- Department of Biomedical Sciences Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Luciana C Veiras
- Department of Biomedical Sciences Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Duo-Yao Cao
- Department of Biomedical Sciences Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Suguru Saito
- Department of Biomedical Sciences Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Zakir Khan
- Department of Biomedical Sciences Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ellen A Bernstein
- Department of Biomedical Sciences Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jorge F Giani
- Department of Biomedical Sciences Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - W Robert Taylor
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA; Division of Cardiology, Atlanta VA Medical Center, Decatur, GA, USA
| | - Kenneth E Bernstein
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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50
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Poulsen SB, Fenton RA. K
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and the renin–angiotensin–aldosterone system: new insights into their role in blood pressure control and hypertension treatment. J Physiol 2019; 597:4451-4464. [DOI: 10.1113/jp276844] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 05/17/2019] [Indexed: 12/11/2022] Open
Affiliation(s)
- Søren B. Poulsen
- Department of BiomedicineAarhus University Aarhus DK‐8000 Denmark
| | - Robert A. Fenton
- Department of BiomedicineAarhus University Aarhus DK‐8000 Denmark
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